Advertisement

T Cell Reprogramming Against Cancer

  • Samuel G. Katz
  • Peter M. RabinovichEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2097)

Abstract

Advances in academic and clinical studies during the last several years have resulted in practical outcomes in adoptive immune therapy of cancer. Immune cells can be programmed with molecular modules that increase their therapeutic potency and specificity. It has become obvious that successful immunotherapy must take into account the full complexity of the immune system and, when possible, include the use of multifactor cell reprogramming that allows fast adjustment during the treatment. Today, practically all immune cells can be stably or transiently reprogrammed against cancer. Here, we review works related to T cell reprogramming, as the most developed field in immunotherapy. We discuss factors that determine the specific roles of αβ and γδ T cells in the immune system and the structure and function of T cell receptors in relation to other structures involved in T cell target recognition and immune response. We also discuss the aspects of T cell engineering, specifically the construction of synthetic T cell receptors (synTCRs) and chimeric antigen receptors (CARs) and the use of engineered T cells in integrative multifactor therapy of cancer.

Keywords

T cell T cell receptor (TCR) Chimeric antigen receptor (CAR) alpha beta T cells gamma delta T cells Memory T cells Immune synapse Reprogramming Adoptive cell therapy Signal transduction TCR clustering 

Notes

Acknowledgment

Sources of Support: NIH R21CA198561, NIH R21AI121993, and Alliance for Cancer Gene Therapy.

References

  1. 1.
    Harrer DC, Dorrie J, Schaft N (2018) Chimeric antigen receptors in different cell types: new vehicles join the race. Hum Gene Ther 29(5):547–558.  https://doi.org/10.1089/hum.2017.236CrossRefPubMedGoogle Scholar
  2. 2.
    Rotolo R, Leuci V, Donini C, Cykowska A, Gammaitoni L, Medico G, Valabrega G, Aglietta M, Sangiolo D (2019) CAR-based strategies beyond T lymphocytes: integrative opportunities for cancer adoptive immunotherapy. Int J Mol Sci 20(11):2839.  https://doi.org/10.3390/ijms20112839CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Mehta RS, Rezvani K (2018) Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front Immunol 9:283.  https://doi.org/10.3389/fimmu.2018.00283CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cassetta L, Kitamura T (2018) Macrophage targeting: opening new possibilities for cancer immunotherapy. Immunology 155(3):285–293.  https://doi.org/10.1111/imm.12976CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Morrissey MA, Williamson AP, Steinbach AM, Roberts EW, Kern N, Headley MB, Vale RD (2018) Chimeric antigen receptors that trigger phagocytosis. elife 7:e36688.  https://doi.org/10.7554/eLife.36688CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Jurgens B, Clarke NS (2019) Evolution of CAR T-cell immunotherapy in terms of patenting activity. Nat Biotechnol 37(4):370–375.  https://doi.org/10.1038/s41587-019-0083-5CrossRefPubMedGoogle Scholar
  7. 7.
    Boyiadzis MM, Dhodapkar MV, Brentjens RJ, Kochenderfer JN, Neelapu SS, Maus MV, Porter DL, Maloney DG, Grupp SA, Mackall CL, June CH, Bishop MR (2018) Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J Immunother Cancer 6(1):137.  https://doi.org/10.1186/s40425-018-0460-5CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    EMA (2018) First two CAR-T cell medicines recommended for approval in the European Union. European Medicines Agency, AmsterdamGoogle Scholar
  9. 9.
    Di Rosa F, Pabst R (2005) The bone marrow: a nest for migratory memory T cells. Trends Immunol 26(7):360–366.  https://doi.org/10.1016/j.it.2005.04.011CrossRefPubMedGoogle Scholar
  10. 10.
    Dhodapkar MV, Kumar V (2017) Type II NKT cells and their emerging role in health and disease. J Immunol 198(3):1015–1021PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Fan X, Rudensky AY (2016) Hallmarks of tissue-resident lymphocytes. Cell 164(6):1198–1211.  https://doi.org/10.1016/j.cell.2016.02.048CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Godfrey DI, Uldrich AP, McCluskey J, Rossjohn J, Moody DB (2015) The burgeoning family of unconventional T cells. Nat Immunol 16(11):1114–1123PubMedCrossRefGoogle Scholar
  13. 13.
    Ziegler H, Welker C, Sterk M, Haarer J, Rammensee HG, Handgretinger R, Schilbach K (2014) Human peripheral CD4(+) Vdelta1(+) gammadeltaT cells can develop into alphabetaT cells. Front Immunol 5:645.  https://doi.org/10.3389/fimmu.2014.00645CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zou C, Zhao P, Xiao Z, Han X, Fu F, Fu L (2017) gammadelta T cells in cancer immunotherapy. Oncotarget 8(5):8900–8909.  https://doi.org/10.18632/oncotarget.13051CrossRefPubMedGoogle Scholar
  15. 15.
    Khairallah C, Chu TH, Sheridan BS (2018) Tissue adaptations of memory and tissue-resident gamma delta T cells. Front Immunol 9:2636.  https://doi.org/10.3389/fimmu.2018.02636CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Alcover A, Alarcon B, Bartolo VD (2018) Cell biology of T cell receptor expression and regulation. Annu Rev Immunol 36:103–125.  https://doi.org/10.1146/annurev-immunol-042617-053429CrossRefPubMedGoogle Scholar
  17. 17.
    Stritesky GL, Jameson SC, Hogquist KA (2012) Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30:95–114PubMedCrossRefGoogle Scholar
  18. 18.
    Serroukh Y, Gu-Trantien C, Hooshiar Kashani B, Defrance M, Vu Manh TP, Azouz A, Detavernier A, Hoyois A, Das J, Bizet M, Pollet E, Tabbuso T, Calonne E, van Gisbergen K, Dalod M, Fuks F, Goriely S, Marchant A (2018) The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes. Elife 7:e30496.  https://doi.org/10.7554/eLife.30496CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R, Naoe Y, Reis BS, Huang Y, Lambolez F, Docherty M, Attinger A, Shui JW, Kim G, Lena CJ, Sakaguchi S, Miyamoto C, Wang P, Atarashi K, Park Y, Nakayama T, Honda K, Ellmeier W, Kronenberg M, Taniuchi I, Cheroutre H (2013) Transcriptional reprogramming of mature CD4(+) helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 14(3):281–289.  https://doi.org/10.1038/ni.2523CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Takeuchi A, Saito T (2017) CD4 CTL, a cytotoxic subset of CD4+ T cells, their differentiation and function. Front Immunol 8:194PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Oja AE, Vieira Braga FA, Remmerswaal EBM, Kragten NAM, Hertoghs KML, Zuo J, Moss PA, van Lier RAW, van Gisbergen KPJM, Hombrink P (2017) The transcription factor Hobit identifies human cytotoxic CD4+ T cells. Front Immunol 8:325PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Hombach A, Kohler H, Rappl G, Abken H (2006) Human CD4+ T cells lyse target cells via granzyme/perforin upon circumvention of MHC class II restriction by an antibody-like immunoreceptor. J Immunol 177(8):5668–5675PubMedCrossRefGoogle Scholar
  23. 23.
    Raeber ME, Zurbuchen Y, Impellizzieri D, Boyman O (2018) The role of cytokines in T-cell memory in health and disease. Immunol Rev 283(1):176–193.  https://doi.org/10.1111/imr.12644CrossRefGoogle Scholar
  24. 24.
    Kim HR, Mun Y, Lee KS, Park YJ, Park JS, Park JH, Jeon BN, Kim CH, Jun Y, Hyun YM, Kim M, Lee SM, Park CS, Im SH, Jun CD (2018) T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells. Nat Commun 9(1):3630.  https://doi.org/10.1038/s41467-018-06090-8CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Myers DR, Zikherman J, Roose JP (2017) Tonic signals: why do lymphocytes bother? Trends Immunol 38(11):844–857.  https://doi.org/10.1016/j.it.2017.06.010CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Born WK, Kemal Aydintug M, O’Brien RL (2013) Diversity of gammadelta T-cell antigens. Cell Mol Immunol 10(1):13–20.  https://doi.org/10.1038/cmi.2012.45CrossRefPubMedGoogle Scholar
  27. 27.
    Qi Q, Xia M, Hu J, Hicks E, Iyer A, Xiong N, August A (2009) Enhanced development of CD4+ gammadelta T cells in the absence of Itk results in elevated IgE production. Blood 114(3):564–571.  https://doi.org/10.1182/blood-2008-12-196345CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brownlie RJ, Zamoyska R (2013) T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol 13(4):257–269PubMedCrossRefGoogle Scholar
  29. 29.
    Geltink RIK, Kyle RL, Pearce EL (2018) Unraveling the complex interplay between T cell metabolism and function. AnnuRev Immunol 36:461–488.  https://doi.org/10.1146/annurev-immunol-042617-053019PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Kershaw MH, Westwood JA, Darcy PK (2013) Gene-engineered T cells for cancer therapy. Nat Rev Cancer 13(8):525–541.  https://doi.org/10.1038/nrc3565CrossRefPubMedGoogle Scholar
  31. 31.
    Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M, Hammerbeck CD, Popescu F, Xiao Z (2006) Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev 211:81–92.  https://doi.org/10.1111/j.0105-2896.2006.00382.xCrossRefPubMedGoogle Scholar
  32. 32.
    Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K (2005) Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202(5):637–650.  https://doi.org/10.1084/jem.20050821CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wrzesinski C, Restifo NP (2005) Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol 17(2):195–201PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Brenchley JM, Douek DC, Ambrozak DR, Chatterji M, Betts MR, Davis LS, Koup RA (2002) Expansion of activated human naive T-cells precedes effector function. Clin Exp Immunol 130(3):432–440.  https://doi.org/10.1046/j.1365-2249.2002.02015.xCrossRefPubMedGoogle Scholar
  35. 35.
    Jones RG, Pearce EJ (2017) MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity 46(5):730–742.  https://doi.org/10.1016/j.immuni.2017.04.028CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    McLean AR, Michie CA (1995) In vivo estimates of division and death rates of human T lymphocytes. Proc Natl Acad Sci U S A 92(9):3707–3711.  https://doi.org/10.1073/pnas.92.9.3707CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bains I, Antia R, Callard R, Yates AJ (2009) Quantifying the development of the peripheral naive CD4+ T-cell pool in humans. Blood 113(22):5480–5487.  https://doi.org/10.1182/blood-2008-10-184184CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    De Boer RJ, Homann D, Perelson AS (2003) Different dynamics of CD4+ and CD8+ T cell responses during and after acute lymphocytic choriomeningitis virus infection. J Immunol 171(8):3928–3935PubMedCrossRefGoogle Scholar
  39. 39.
    Yoon H, Kim TS, Braciale TJ (2010) The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus. PLoS One 5(11):e15423PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Arsenio J, Metz PJ, Chang JT (2015) Asymmetric cell division in T lymphocyte fate diversification. Trends Immunol 36(11):670–683.  https://doi.org/10.1016/j.it.2015.09.004PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Pollizzi KN, Sun I-H, Patel CH, Lo Y-C, Oh M-H, Waickman AT, Tam AJ, Blosser RL, Wen J, Delgoffe GM, Powell JD (2016) Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol 17(6):704–711PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    van der Windt GJW, Everts B, Chang C-H, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36(1):68–78PubMedCrossRefGoogle Scholar
  43. 43.
    Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L (2013) Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 123(10):4479–4488PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chapman NM, Chi H (2018) Hallmarks of T-cell exit from quiescence. Cancer Immunol Res 6(5):502–508.  https://doi.org/10.1158/2326-6066.CIR-17-0605CrossRefPubMedGoogle Scholar
  45. 45.
    Martinez-Lostao L, Anel A, Pardo J (2015) How do cytotoxic lymphocytes kill cancer cells? Clin Cancer Res 21(22):5047–5056.  https://doi.org/10.1158/1078-0432.CCR-15-0685CrossRefPubMedGoogle Scholar
  46. 46.
    Masaki Y, Ohminami H, Arai J, Kasahara Y, Ishida Y, Fujita S (2002) Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD41 as well as CD81 cytotoxic T lymphocytes in humans. Blood 95(7):2352–2356Google Scholar
  47. 47.
    Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S (2019) Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci 20(6):E1283.  https://doi.org/10.3390/ijms20061283CrossRefPubMedGoogle Scholar
  48. 48.
    Cullen SP, Martin SJ (2008) Mechanisms of granule-dependent killing. Cell Death Differ 15(2):251–262.  https://doi.org/10.1038/sj.cdd.4402244CrossRefPubMedGoogle Scholar
  49. 49.
    de Saint Basile G, Menasche G, Fischer A (2010) Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 10(8):568–579.  https://doi.org/10.1038/nri2803CrossRefPubMedGoogle Scholar
  50. 50.
    Zhan Y, Carrington EM, Zhang Y, Heinzel S, Lew AM (2017) Life and death of activated T cells: how are they different from naive T cells? Front Immunol 8:1809.  https://doi.org/10.3389/fimmu.2017.01809CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Malyshkina A, Littwitz-Salomon E, Sutter K, Zelinskyy G, Windmann S, Schimmer S, Paschen A, Streeck H, Hasenkrug KJ, Dittmer U (2017) Fas Ligand-mediated cytotoxicity of CD4+ T cells during chronic retrovirus infection. Sci Rep 7(1):7785.  https://doi.org/10.1038/s41598-017-08578-7CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mirandola P, Ponti C, Gobbi G, Sponzilli I, Vaccarezza M, Cocco L, Zauli G, Secchiero P, Manzoli FA, Vitale M (2004) Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity. Blood 104(8):2418–2424PubMedCrossRefGoogle Scholar
  53. 53.
    Marrack P, Scott-Browne J, MacLeod MK (2010) Terminating the immune response. Immunol Rev 236:5–10.  https://doi.org/10.1111/j.1600-065X.2010.00928.xCrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712PubMedCrossRefGoogle Scholar
  55. 55.
    Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291(5512):2413–2417PubMedCrossRefGoogle Scholar
  56. 56.
    Macallan DC, Wallace D, Zhang Y, De Lara C, Worth AT, Ghattas H, Griffin GE, Beverley PCL, Tough DF (2004) Rapid turnover of effector-memory CD4(+) T cells in healthy humans. J Exp Med 200(2):255–260PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Amsen D, van Gisbergen KPJM, Hombrink P, van Lier RAW (2018) Tissue-resident memory T cells at the center of immunity to solid tumors. Nat Immunol 19(6):538–546PubMedCrossRefGoogle Scholar
  58. 58.
    Farber DL, Yudanin NA, Restifo NP (2014) Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 14(1):24–35PubMedCrossRefGoogle Scholar
  59. 59.
    Willinger T, Freeman T, Herbert M, Hasegawa H, McMichael AJ, Callan MF (2006) Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo. J Immunol 176(3):1439–1446.  https://doi.org/10.4049/jimmunol.176.3.1439CrossRefPubMedGoogle Scholar
  60. 60.
    Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15(7):808–813.  https://doi.org/10.1038/nm.1982CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP (2011) A human memory T cell subset with stem cell-like properties. Nat Med 17(10):1290–1297.  https://doi.org/10.1038/nm.2446CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Youngblood B, Hale JS, Kissick HT, Ahn E, Xu X, Wieland A, Araki K, West EE, Ghoneim HE, Fan Y, Dogra P, Davis CW, Konieczny BT, Antia R, Cheng X, Ahmed R (2017) Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552(7685):404–409PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Schenkel JM, Masopust D (2014) Tissue-resident memory T cells. Immunity 41(6):886–897PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Martin MD, Badovinac VP (2018) Defining memory CD8 T cell. Front Immunol 9:2692.  https://doi.org/10.3389/fimmu.2018.02692CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lugli E, Gattinoni L, Roberto A, Mavilio D, Price DA, Restifo NP, Roederer M (2013) Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat Protoc 8(1):33–42PubMedCrossRefGoogle Scholar
  66. 66.
    Kawabe T, Jankovic D, Kawabe S, Huang Y, Lee PH, Yamane H, Zhu J, Sher A, Germain RN, Paul WE (2017) Memory-phenotype CD4(+) T cells spontaneously generated under steady-state conditions exert innate TH1-like effector function. Sci Immunol 2(12).  https://doi.org/10.1126/sciimmunol.aam9304PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Demissie E, Mahajan VS, Alsufyani F, Kumari S, Yuen GJ, Viswanadham V, Tran JQ, Moon JJ, Irvine DJ, Pillai S (2019) DOCK2 sets the threshold for entry into the virtual memory CD8+ T cell compartment by negatively regulating tonic TCR triggering. bioRXiv. https://doi.org/10.1101/582486
  68. 68.
    White JT, Cross EW, Burchill MA, Danhorn T, McCarter MD, Rosen HR, O’Connor B, Kedl RM (2016) Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun 7:11291PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Anthony SM, Howard ME, Hailemichael Y, Overwijk WW, Schluns KS (2015) Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways. PLoS One 10(3):e0120274PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Geginat J, Sallusto F, Lanzavecchia A (2001) Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells. J Exp Med 194(12):1711–1719PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Westermann J, Bode U, Sahle A, Speck U, Karin N, Bell EB, Kalies K, Gebert A (2005) Naive, effector, and memory T lymphocytes efficiently scan dendritic cells in vivo: contact frequency in T cell zones of secondary lymphoid organs does not depend on LFA-1 expression and facilitates survival of effector T cells. J Immunol 174(5):2517–2524PubMedCrossRefGoogle Scholar
  72. 72.
    Nolz JC, Rai D, Badovinac VP, Harty JT (2012) Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells. Proc Natl Acad Sci U S A 109(16):6199–6204PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Vrisekoop N, den Braber I, de Boer AB, Ruiter AFC, Ackermans MT, van der Crabben SN, Schrijver EHR, Spierenburg G, Sauerwein HP, Hazenberg MD, de Boer RJ, Miedema F, Borghans JAM, Tesselaar K (2008) Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool. Proc Natl Acad Sci U S A 105(16):6115–6120PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Biasco L, Scala S, Basso Ricci L, Dionisio F, Baricordi C, Calabria A, Giannelli S, Cieri N, Barzaghi F, Pajno R, Al-Mousa H, Scarselli A, Cancrini C, Bordignon C, Roncarolo MG, Montini E, Bonini C, Aiuti A (2015) In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med 7(273):273ra213CrossRefGoogle Scholar
  75. 75.
    Oliveira G, Ruggiero E, Stanghellini MTL, Cieri N, D’Agostino M, D’Agostino M, Fronza R, Lulay C, Dionisio F, Mastaglio S, Greco R, Peccatori J, Aiuti A, Ambrosi A, Biasco L, Bondanza A, Lambiase A, Traversari C, Vago L, von Kalle C, Schmidt M, Bordignon C, Ciceri F, Bonini C (2015) Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci Transl Med 7(317):317ra198PubMedCrossRefGoogle Scholar
  76. 76.
    Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95(9):2860–2868PubMedCrossRefGoogle Scholar
  77. 77.
    Naylor K, Li G, Vallejo AN, Lee W-W, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174(11):7446–7452PubMedCrossRefGoogle Scholar
  78. 78.
    Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA (2008) Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 205(3):711–723PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Puellmann K, Kaminski WE, Vogel M, Nebe CT, Schroeder J, Wolf H, Beham AW (2006) A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci U S A 103(39):14441–14446.  https://doi.org/10.1073/pnas.0603406103CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Fuchs T, Puellmann K, Scharfenstein O, Eichner R, Stobe E, Becker A, Pechlivanidou I, Kzhyshkowska J, Gratchev A, Ganser A, Neumaier M, Beham AW, Kaminski WE (2012) The neutrophil recombinatorial TCR-like immune receptor is expressed across the entire human life span but repertoire diversity declines in old age. Biochem Biophys Res Commun 419(2):309–315.  https://doi.org/10.1016/j.bbrc.2012.02.017CrossRefPubMedGoogle Scholar
  81. 81.
    Fuchs T, Puellmann K, Emmert A, Fleig J, Oniga S, Laird R, Heida NM, Schafer K, Neumaier M, Beham AW, Kaminski WE (2015) The macrophage-TCRalphabeta is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis. Biochem Biophys Res Commun 456(1):59–65.  https://doi.org/10.1016/j.bbrc.2014.11.034CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Kao RL, Truscott LC, Chiou TT, Tsai W, AM W, De Oliveira SN (2019) Cetuximab-mediated suicide system in chimeric antigen receptor-modified hematopoietic stem cells for cancer therapy. Hum Gene Ther 30(4):413–428PubMedCrossRefGoogle Scholar
  83. 83.
    Brazin KN, Mallis RJ, Boeszoermenyi A, Feng Y, Yoshizawa A, Reche PA, Kaur P, Bi K, Hussey RE, Duke-Cohan JS, Song L, Wagner G, Arthanari H, Lang MJ, Reinherz EL (2018) The T cell antigen receptor alpha transmembrane domain coordinates triggering through regulation of Bilayer immersion and CD3 subunit associations. Immunity 49(5):829–841.e826.  https://doi.org/10.1016/j.immuni.2018.09.007CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Wucherpfennig KW, Gagnon E, Call MJ, Huseby ES, Call ME (2010) Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb Perspect Biol 2(4):a005140.  https://doi.org/10.1101/cshperspect.a005140CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Call ME, Wucherpfennig KW (2004) Molecular mechanisms for the assembly of the T cell receptor-CD3 complex. Mol Immunol 40(18):1295–1305.  https://doi.org/10.1016/j.molimm.2003.11.017CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Love PE, Hayes SM (2010) ITAM-mediated signaling by the T-cell antigen receptor. Cold Spring Harb Perspect Biol 2(6):a002485.  https://doi.org/10.1101/cshperspect.a002485CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Park S, Krshnan L, Call MJ, Call ME, Im W (2018) Structural conservation and effects of alterations in T cell receptor transmembrane interfaces. Biophys J 114(5):1030–1035.  https://doi.org/10.1016/j.bpj.2018.01.004CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Deswal S, Schamel WWA (2012) CD3ζ. In: Choi S (ed) Encyclopedia of signaling molecules. Springer, New York, pp 294–314. https://doi.org/10.1007/978-1-4419-0461-4CrossRefGoogle Scholar
  89. 89.
    Rojo JM, Portoles P (1991) A symmetrical view of the T-cell receptor-CD3 complex. Immunol Today 12(10):377–378PubMedCrossRefGoogle Scholar
  90. 90.
    Schamel WW, Alarcon B (2013) Organization of the resting TCR in nanoscale oligomers. Immunol Rev 251(1):13–20.  https://doi.org/10.1111/imr.12019CrossRefPubMedGoogle Scholar
  91. 91.
    Exley M, Wileman T, Mueller B, Terhorst C (1995) Evidence for multivalent structure of T-cell antigen receptor complex. Mol Immunol 32(11):829–839PubMedCrossRefGoogle Scholar
  92. 92.
    Fernandez-Miguel G, Alarcon B, Iglesias A, Bluethmann H, Alvarez-Mon M, Sanz E, de la Hera A (1999) Multivalent structure of an alphabetaT cell receptor. Proc Natl Acad Sci U S A 96(4):1547–1552.  https://doi.org/10.1073/pnas.96.4.1547CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Balagopalan L, Sherman E, Barr VA, Samelson LE (2011) Imaging techniques for assaying lymphocyte activation in action. Nat Rev Immunol 11(1):21–33.  https://doi.org/10.1038/nri2903CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Lee K-H, Dinner AR, Tu C, Campi G, Raychaudhuri S, Varma R, Sims TN, Burack WR, Wu H, Wang J, Kanagawa O, Markiewicz M, Allen PM, Dustin ML, Chakraborty AK, Shaw AS (2003) The immunological synapse balances T cell receptor signaling and degradation. Science 302(5648):1218–1222PubMedCrossRefGoogle Scholar
  95. 95.
    Eleftheriadis T, Kartsios C, Yiannaki E, Kazila P, Antoniadi G, Liakopoulos V, Markala D (2008) Chronic inflammation and CD16+ natural killer cell zeta-chain downregulation in hemodialysis patients. Blood Purif 26(4):317–321.  https://doi.org/10.1159/000130068CrossRefPubMedGoogle Scholar
  96. 96.
    Baudouin SJ, Angibaud J, Loussouarn G, Bonnamain V (2008) The signaling adaptor protein CD3ζ is a negative regulator dendrite development young neurons. Mol Biol Cell 19:2444–2456.  https://doi.org/10.1091/mbc.E07-09-0947CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Krshnan L, Park S, Im W, Call MJ, Call ME (2016) A conserved alphabeta transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane. Proc Natl Acad Sci U S A 113(43):E6649–E6658.  https://doi.org/10.1073/pnas.1611445113CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD, Carman CV, Chou JJ, Wucherpfennig KW (2008) Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 135(4):702–713.  https://doi.org/10.1016/j.cell.2008.09.044CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Gagnon E, Schubert DA, Gordo S, Chu HH, Wucherpfennig KW (2012) Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3epsilon cytoplasmic domain. J Exp Med 209(13):2423–2439.  https://doi.org/10.1084/jem.20120790CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Wang JH, Reinherz EL (2012) The structural basis of alphabeta T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol Rev 250(1):102–119.  https://doi.org/10.1111/j.1600-065X.2012.01161.xCrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Minguet S, Schamel WW (2008) A permissive geometry model for TCR-CD3 activation. Trends Biochem Sci 33(2):51–57.  https://doi.org/10.1016/j.tibs.2007.10.008CrossRefPubMedGoogle Scholar
  102. 102.
    Zhang H, Cordoba SP, Dushek O, van der Merwe PA (2011) Basic residues in the T-cell receptor zeta cytoplasmic domain mediate membrane association and modulate signaling. Proc Natl Acad Sci U S A 108(48):19323–19328.  https://doi.org/10.1073/pnas.1108052108CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Paensuwan P, Hartl FA, Yousefi OS, Ngoenkam J, Wipa P, Beck-Garcia E, Dopfer EP, Khamsri B, Sanguansermsri D, Minguet S, Schamel WW, Pongcharoen S (2016) Nck binds to the T cell antigen receptor using its SH3.1 and SH2 domains in a cooperative manner, promoting TCR functioning. J Immunol 196(1):448–458PubMedCrossRefGoogle Scholar
  104. 104.
    Holst J, Wang H, Eder KD, Workman CJ, Boyd KL, Baquet Z, Singh H, Forbes K, Chruscinski A, Smeyne R, van Oers NSC, Utz PJ, Vignali DAA (2008) Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat Immunol 9(6):658–666PubMedCrossRefGoogle Scholar
  105. 105.
    Guy CS, Vignali KM, Temirov J, Bettini ML, Overacre AE, Smeltzer M, Zhang H, Huppa JB, Tsai Y-H, Lobry C, Xie J, Dempsey PJ, Crawford HC, Aifantis I, Davis MM, Vignali DAA (2013) Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol 14(3):262–270PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    James JR (2018) Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci Signal 11(531):eaan1088.  https://doi.org/10.1126/scisignal.aan1088CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O (2013) Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity. PLoS Comput Biol 9(3):e1003004.  https://doi.org/10.1371/journal.pcbi.1003004CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R (2009) T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev 228(1):9–22PubMedCrossRefGoogle Scholar
  109. 109.
    Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4(3):248–254PubMedCrossRefGoogle Scholar
  110. 110.
    van Oers NS, Tohlen B, Malissen B, Moomaw CR, Afendis S, Slaughter CA (2000) The 21- and 23-kD forms of TCR zeta are generated by specific ITAM phosphorylations. Nat Immunol 1(4):322–328.  https://doi.org/10.1038/79774CrossRefPubMedGoogle Scholar
  111. 111.
    Vely F, Nunes JA, Malissen B, Hedgecock CJ (1997) Analysis of immunoreceptor tyrosine-based activation motif (ITAM) binding to ZAP-70 by surface plasmon resonance. Eur J Immunol 27(11):3010–3014.  https://doi.org/10.1002/eji.1830271138CrossRefPubMedGoogle Scholar
  112. 112.
    Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A (2010) ZAP-70: an essential kinase in T-cell signaling. Cold Spring Harb Perspect Biol 2:a002279.  https://doi.org/10.1101/cshperspect.a002279CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Pitcher LA, van Oers NSC (2003) T-cell receptor signal transmission: who gives an ITAM? Trends Immunol 24(10):554–560.  https://doi.org/10.1016/j.it.2003.08.003CrossRefPubMedGoogle Scholar
  114. 114.
    Courtney AH, Lo WL, Weiss A (2018) TCR signaling: mechanisms of initiation and propagation. Trends Biochem Sci 43(2):108–123.  https://doi.org/10.1016/j.tibs.2017.11.008CrossRefPubMedGoogle Scholar
  115. 115.
    Proust R, Bertoglio J, Gesbert F (2012) The adaptor protein SAP directly associates with CD3zeta chain and regulates T cell receptor signaling. PLoS One 7(8):e43200.  https://doi.org/10.1371/journal.pone.0043200CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Gil D, Schamel WWA, Montoya M, Sanchez-Madrid F, Alarcon B (2002) Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109(7):901–912PubMedCrossRefGoogle Scholar
  117. 117.
    Kazi JU, Kabir NN, Ronnstrand L (2015) Role of SRC-like adaptor protein (SLAP) in immune and malignant cell signaling. Cell Mol Life Sci 72(13):2535–2544.  https://doi.org/10.1007/s00018-015-1882-6CrossRefPubMedGoogle Scholar
  118. 118.
    Sosinowski T, Pandey A, Dixit VM, Weiss A (2000) Src-like adaptor protein (SLAP) is a negative regulator of T cell receptor signaling. J Exp Med 191:463–473PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Myers MD, Dragone LL, Weiss A (2005) Src-like adaptor protein down-regulates T cell receptor (TCR)-CD3 expression by targeting TCRzeta for degradation. J Cell Biol 170(2):285–294.  https://doi.org/10.1083/jcb.200501164CrossRefPubMedCentralPubMedGoogle Scholar
  120. 120.
    Ksionda O, Saveliev A, Kochl R, Rapley J, Faroudi M, Smith-Garvin JE, Wulfing C, Rittinger K, Carter T, Tybulewicz VLJ (2012) Mechanism and function of Vav1 localisation in TCR signalling. J Cell Sci 125(Pt 22):5302–5314PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Lewis JB, Scangarello FA, Murphy JM, Eidell KP, Sodipo MO, Ophir MJ, Sargeant R, Seminario M-C, Bunnell SC (2018) ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters. J Cell Sci 131(21).  https://doi.org/10.1242/jcs.215517PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Yousefi OS, Gunther M, Horner M, Chalupsky J, Wess M, Brandl SM, Smith RW, Fleck C, Kunkel T, Zurbriggen MD, Hofer T, Weber W, Schamel WW (2019) Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor. Elife 8.  https://doi.org/10.7554/eLife.42475
  123. 123.
    Stefanova I, Dorfman J, Germain R (2002) Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420(6914):429–434PubMedCrossRefGoogle Scholar
  124. 124.
    Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC, Thomas ML (1996) Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science 272(5265):1173–1176PubMedCrossRefGoogle Scholar
  125. 125.
    Artyomov MN, Lis M, Devadas S, Davis MM, Chakraborty AK (2010) CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. Proc Natl Acad Sci U S A 107(39):16916–16921.  https://doi.org/10.1073/pnas.1010568107CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Li Q-J, Dinner AR, Qi S, Irvine DJ, Huppa JB, Davis MM, Chakraborty AK (2004) CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat Immunol 5(8):791–799PubMedCrossRefGoogle Scholar
  127. 127.
    Moody AM, Chui D, Reche PA, Priatel JJ, Marth JD, Reinherz EL (2001) Developmentally regulated glycosylation of the CD8alphabeta coreceptor stalk modulates ligand binding. Cell 107(4):501–512PubMedCrossRefGoogle Scholar
  128. 128.
    Williams CM, Schonnesen AA, Zhang S-Q, Ma K-Y, He C, Yamamoto T, Eckhardt SG, Klebanoff CA, Jiang N (2017) Normalized synergy predicts that CD8 co-receptor contribution to T cell receptor (TCR) and pMHC binding decreases as TCR affinity increases in human viral-specific T cells. Front Immunol 8:894PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Au-Yeung BB, Levin SE, Zhang C, Hsu L-Y, Cheng DA, Killeen N, Shokat KM, Weiss A (2010) A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity. Nat Immunol 11(12):1085–1092PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Comrie WA, Burkhardt JK (2016) Action and traction: cytoskeletal control of receptor triggering at the immunological synapse. Front Immunol 7:68PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Steinbuck MP, Arakcheeva K, Winandy S (2018) Novel TCR-mediated mechanisms of notch activation and signaling. J Immunol 200(3):997–1007.  https://doi.org/10.4049/jimmunol.1700070CrossRefPubMedGoogle Scholar
  132. 132.
    Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35(6):871–882PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Scholz G, Jandus C, Zhang L, Grandclement C, Lopez-Mejia IC, Soneson C, Delorenzi M, Fajas L, Held W, Dormond O, Romero P (2016) Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells. EBioMedicine 4:50–61.  https://doi.org/10.1016/j.ebiom.2016.01.019CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5(6):472–484PubMedCrossRefGoogle Scholar
  135. 135.
    Cockerill PN (2016) Receptor signaling directs global recruitment of pre-existing transcription factors to inducible elements. Yale J Biol Med 89(4):591–596PubMedPubMedCentralGoogle Scholar
  136. 136.
    Tan MP, Dolton GM, Gerry AB, Brewer JE, Bennett AD, Pumphrey NJ, Jakobsen BK, Sewell AK (2017) Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells. Clin Exp Immunol 187(1):124–137PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    de la Roche M, Asano Y, Griffiths GM (2016) Origins of the cytolytic synapse. Nat Rev Immunol 16(7):421–432PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Schuijs MJ, Hammad H, Lambrecht BN (2019) Professional and ‘amateur’ antigen-presenting cells in type 2 immunity. Trends Immunol 40(1):22–34PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Lin A, Lore K (2017) Granulocytes: new members of the antigen-presenting cell family. Front Immunol 8:1781PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, Liblau R, Makinen T, Engelhard VH (2015) Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat Commun 6:6771PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Kambayashi T, Laufer TM (2014) Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol 14(11):719–730PubMedCrossRefGoogle Scholar
  142. 142.
    Verboogen DRJ, Dingjan I, Revelo NH, Visser LJ, ter Beest M, van den Bogaart G (2016) The dendritic cell side of the immunological synapse. Biomol Concepts 7(1):17–28PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Rodriguez-Fernandez JL, Riol-Blanco L, Delgado-Martin C (2010) What is the function of the dendritic cell side of the immunological synapse? Sci Signal 3(105):re2PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Fisher PJ, Bulur PA, Vuk-Pavlovic S, Prendergast FG, Dietz AB (2008) Dendritic cell microvilli: a novel membrane structure associated with the multifocal synapse and T-cell clustering. Blood 112(13):5037–5045PubMedCrossRefGoogle Scholar
  145. 145.
    Ronchese F, Hermans IF (2001) Killing of dendritic cells: a life cut short or a purposeful death? J Exp Med 194(5):F23–F26PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Brockman JM, Salaita K (2019) Mechanical proofreading: a general mechanism to enhance the fidelity of information transfer between cells. Front Phys 7.  https://doi.org/10.3389/fphy.2019.00014
  147. 147.
    Legut M, Cole DK, Sewell AK (2015) The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol 12(6):656–668.  https://doi.org/10.1038/cmi.2015.28CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Sharma P, Kranz DM (2016) Recent advances in T-cell engineering for use in immunotherapy. F1000Res 5Google Scholar
  149. 149.
    Davenport AJ, Cross RS, Watson KA, Liao Y, Shi W, Prince HM, Beavis PA, Trapani JA, Kershaw MH, Ritchie DS, Darcy PK, Neeson PJ, Jenkins MR (2018) Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc Natl Acad Sci U S A 115(9):E2068–E2076PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    van der Merwe PA, Dushek O (2011) Mechanisms for T cell receptor triggering. Nat Rev Immunol 11(1):47–55.  https://doi.org/10.1038/nri2887CrossRefPubMedGoogle Scholar
  151. 151.
    Siller-Farfan JA, Dushek O (2018) Molecular mechanisms of T cell sensitivity to antigen. Immunol Rev 285(1):194–205PubMedCrossRefGoogle Scholar
  152. 152.
    Boniface JJ, Rabinowitz JD, Wulfing C, Hampl J, Reich Z, Altman JD, Kantor RM, Beeson C, McConnell HM, Davis MM (1998) Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected]. Immunity 9(4):459–466PubMedCrossRefGoogle Scholar
  153. 153.
    Grossman Z, Paul WE (2015) Dynamic tuning of lymphocytes: physiological basis, mechanisms, and function. Annu Rev Immunol 33:677–713.  https://doi.org/10.1146/annurev-immunol-032712-100027CrossRefPubMedGoogle Scholar
  154. 154.
    Cho JH, Sprent J (2018) TCR tuning of T cell subsets. Immunol Rev 283(1):129–137.  https://doi.org/10.1111/imr.12646CrossRefPubMedGoogle Scholar
  155. 155.
    Azzam HS, DeJarnette JB, Huang K, Emmons R, Park CS, Sommers CL, El-Khoury D, Shores EW, Love PE (2001) Fine tuning of TCR signaling by CD5. J Immunol 166(9):5464–5472PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Park J-H, Adoro S, Lucas PJ, Sarafova SD, Alag AS, Doan LL, Erman B, Liu X, Ellmeier W, Bosselut R, Feigenbaum L, Singer A (2007) ‘Coreceptor tuning’: cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol 8(10):1049–1059PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Thomas S, Xue SA, Bangham CR, Jakobsen BK, Morris EC, Stauss HJ (2011) Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen. Blood 118(2):319–329.  https://doi.org/10.1182/blood-2010-12-326736CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Junghans V, Santos AM, Lui Y, Davis SJ, Jonsson P (2018) Dimensions and interactions of large T-cell surface proteins. Front Immunol 9:2215PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Jung Y, Riven I, Feigelson SW, Kartvelishvily E, Tohya K, Miyasaka M, Alon R, Haran G (2016) Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies. Proc Natl Acad Sci U S A 113(40):E5916–E5924PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Sage PT, Varghese LM, Martinelli R, Sciuto TE, Kamei M, Dvorak AM, Springer TA, Sharpe AH, Carman CV (2012) Antigen recognition is facilitated by invadosome-like protrusions formed by memory/effector T cells. J Immunol 188(8):3686–3699PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Varma R, Campi G, Yokosuka T, Saito T, Dustin ML (2006) T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25(1):117–127PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Shaw AS, Dustin ML (1997) Making the T cell receptor go the distance: a topological view of T cell activation. Immunity 6(4):361–369PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Dustin ML (2014) The immunological synapse. Cancer Immunol Res 2(11):1023–1033PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Sadreddini S, Baradaran B, Aghebati-Maleki A, Sadreddini S, Shanehbandi D, Fotouhi A, Aghebati-Maleki L (2019) Immune checkpoint blockade opens a new way to cancer immunotherapy. J Cell Physiol 234(6):8541–8549PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553.  https://doi.org/10.1128/MCB.25.21.9543-9553.2005CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355(6332):1428–1433.  https://doi.org/10.1126/science.aaf1292CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Walker LSK (2017) PD-1 and CTLA4: two checkpoints, one pathway? Sci Immunol 2(11).  https://doi.org/10.1126/sciimmunol.aan3864PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Walker LSK, Sansom DM (2015) Confusing signals: recent progress in CTLA-4 biology. Trends Immunol 36(2):63–70PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Hivroz C, Chemin K, Tourret M, Bohineust A (2012) Crosstalk between T lymphocytes and dendritic cells. Crit Rev Immunol 32(2):139–155PubMedCrossRefGoogle Scholar
  170. 170.
    Watchmaker PB, Urban JA, Berk E, Nakamura Y, Mailliard RB, Watkins SC, van Ham SM, Kalinski P (2008) Memory CD8+ T cells protect dendritic cells from CTL killing. J Immunol 180(6):3857–3865PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Zarour HM (2016) Reversing T-cell dysfunction and exhaustion in cancer. Clin Cancer Res 22(8):1856–1864.  https://doi.org/10.1158/1078-0432.CCR-15-1849CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Grywalska E, Pasiarski M, Gozdz S, Rolinski J (2018) Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer. Onco Targets Ther 11:6505–6524.  https://doi.org/10.2147/OTT.S150817CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10(7):505–514.  https://doi.org/10.1038/nrc2868CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Aptsiauri N, Cabrera T, Mendez R, Garcia-Lora A, Ruiz-Cabello F, Garrido F (2007) Role of altered expression of HLA class I molecules in cancer progression. Adv Exp Med Biol 601:123–131.  https://doi.org/10.1007/978-0-387-72005-0_13CrossRefGoogle Scholar
  175. 175.
    Gao D, Jiang L (2018) Exosomes in cancer therapy: a novel experimental strategy. Am J Cancer Res 8(11):2165–2175PubMedPubMedCentralGoogle Scholar
  176. 176.
    Andrews MC, Reuben A, Gopalakrishnan V, Wargo JA (2018) Concepts collide: genomic, immune, and microbial influences on the tumor microenvironment and response to cancer therapy. Front Immunol 9:946.  https://doi.org/10.3389/fimmu.2018.00946CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Pageon SV, Tabarin T, Yamamoto Y, Ma Y, Nicovich PR, Bridgeman JS, Cohnen A, Benzing C, Gao Y, Crowther MD, Tungatt K, Dolton G, Sewell AK, Price DA, Acuto O, Parton RG, Gooding JJ, Rossy J, Rossjohn J, Gaus K (2016) Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. Proc Natl Acad Sci U S A 113(37):E5454–E5463.  https://doi.org/10.1073/pnas.1607436113CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT, Valpuesta JM, Schamel WW, Alarcon B, van Santen HM (2011) Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes. Immunity 35(3):375–387.  https://doi.org/10.1016/j.immuni.2011.08.010CrossRefPubMedGoogle Scholar
  179. 179.
    Sherman E, Barr V, Manley S, Patterson G, Balagopalan L, Akpan I, Regan CK, Merrill RK, Sommers CL, Lippincott-Schwartz J, Samelson LE (2011) Functional nanoscale organization of signaling molecules downstream of the T cell antigen receptor. Immunity 35(5):705–720.  https://doi.org/10.1016/j.immuni.2011.10.004CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Schamel WW, Alarcon B, Hofer T, Minguet S (2017) The allostery model of TCR regulation. J Immunol 198(1):47–52.  https://doi.org/10.4049/jimmunol.1601661CrossRefPubMedGoogle Scholar
  181. 181.
    Martin-Blanco N, Blanco R, Alda-Catalinas C, Bovolenta ER, Oeste CL, Palmer E, Schamel WW, Lythe G, Molina-Paris C, Castro M, Alarcon B (2018) A window of opportunity for cooperativity in the T cell receptor. Nat Commun 9(1):2618.  https://doi.org/10.1038/s41467-018-05050-6CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    von Essen MR, Kongsbak M, Geisler C (2012) Mechanisms behind functional avidity maturation in T cells. Clin Dev Immunol 2012:163453Google Scholar
  183. 183.
    Hayes SM, Love PE (2002) Distinct structure and signaling potential of the gamma delta TCR complex. Immunity 16(6):827–838PubMedCrossRefGoogle Scholar
  184. 184.
    Hayes SM, Love PE (2006) Stoichiometry of the murine gammadelta T cell receptor. J Exp Med 203(1):47–52.  https://doi.org/10.1084/jem.20051886CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Dave VP, Cao Z, Browne C et al (1997) CD3 delta deficiency arrests development of the alpha beta but not the gamma delta T cell lineage. EMBO J 16(6):1360–1370PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Siegers GM, Swamy M, Fernandez-Malave E, Minguet S, Rathmann S, Guardo AC, Perez-Flores V, Regueiro JR, Alarcon B, Fisch P, Schamel WW (2007) Different composition of the human and the mouse gammadelta T cell receptor explains different phenotypes of CD3gamma and CD3delta immunodeficiencies. J Exp Med 204(11):2537–2544.  https://doi.org/10.1084/jem.20070782CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Cheng HY, Wu R, Gebre AK, Hanna RN, Smith DJ, Parks JS, Ley K, Hedrick CC (2013) Increased cholesterol content in gammadelta (gammadelta) T lymphocytes differentially regulates their activation. PLoS One 8(5):e63746.  https://doi.org/10.1371/journal.pone.0063746CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Haks MC, Lefebvre JM, Lauritsen JPH, Carleton M, Rhodes M, Miyazaki T, Kappes DJ, Wiest DL (2005) Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage. Immunity 22(5):595–606PubMedCrossRefGoogle Scholar
  189. 189.
    Nicolas L, Monneret G, Debard AL, Blesius A, Gutowski MC, Salles G, Bienvenu J (2001) Human gammadelta T cells express a higher TCR/CD3 complex density than alphabeta T cells. Clin Immunol 98(3):358–363PubMedCrossRefGoogle Scholar
  190. 190.
    Hayes SM, Li L, Love PE (2005) TCR signal strength influences alphabeta/gammadelta lineage fate. Immunity 22(5):583–593PubMedCrossRefGoogle Scholar
  191. 191.
    Dopfer EP, Hartl FA, Oberg HH, Siegers GM, Yousefi OS, Kock S, Fiala GJ, Garcillan B, Sandstrom A, Alarcon B, Regueiro JR, Kabelitz D, Adams EJ, Minguet S, Wesch D, Fisch P, Schamel WWA (2014) The CD3 conformational change in the gammadelta T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing. Cell Rep 7(5):1704–1715.  https://doi.org/10.1016/j.celrep.2014.04.049CrossRefPubMedGoogle Scholar
  192. 192.
    Muro R, Takayanagi H, Nitta T (2019) T cell receptor signaling for gammadeltaT cell development. Inflamm Regen 39:6.  https://doi.org/10.1186/s41232-019-0095-zCrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Laird RM, Laky K, Hayes SM (2010) Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing gammadelta T cells. J Immunol 185(11):6518–6527.  https://doi.org/10.4049/jimmunol.1002766CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Getts D, Hofmeister R, Quintas-Cardama A (2019) Synthetic T cell receptor-based lymphocytes for cancer therapy. Adv Drug Deliv Rev.  https://doi.org/10.1016/j.addr.2019.04.002CrossRefGoogle Scholar
  195. 195.
    Thomas S, Stauss HJ, Morris EC (2010) Molecular immunology lessons from therapeutic T-cell receptor gene transfer. Immunology 129(2):170–177PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    van Loenen MM, de Boer R, Amir AL, Hagedoorn RS, Volbeda GL, Willemze R, van Rood JJ, Falkenburg JHF, Heemskerk MHM (2010) Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci U S A 107(24):10972–10977PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Voss R-H, Willemsen RA, Kuball J, Grabowski M, Engel R, Intan RS, Guillaume P, Romero P, Huber C, Theobald M (2008) Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells. J Immunol 180(1):391–401PubMedCrossRefGoogle Scholar
  198. 198.
    Sommermeyer D, Uckert W (2010) Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells. J Immunol 184(11):6223–6231PubMedCrossRefGoogle Scholar
  199. 199.
    Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA (2006) Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res 66(17):8878–8886PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Rosati S, Parkhurst MR, Hong Y et al (2014) A novel murine T-cell receptor targeting NY-ESO-1. J Immunother 37:135–146PubMedCrossRefGoogle Scholar
  201. 201.
    Legut M, Dolton G, Mian AA, Ottmann OG, Sewell AK (2018) CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood 131(3):311–322.  https://doi.org/10.1182/blood-2017-05-787598CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Ahmadi M, King JW, Xue S-A, Voisine C, Holler A, Wright GP, Waxman J, Morris E, Stauss HJ (2011) CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118(13):3528–3537PubMedCrossRefGoogle Scholar
  203. 203.
    Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, Gavarret J, Bianchi FC, Pumphrey NJ, Ladell K, Gostick E, Sewell AK, Lissin NM, Harwood NE, Molloy PE, Li Y, Cameron BJ, Sami M, Baston EE, Todorov PT, Paston SJ, Dennis RE, Harper JV, Dunn SM, Ashfield R, Johnson A, McGrath Y, Plesa G, June CH, Kalos M, Price DA, Vuidepot A, Williams DD, Sutton DH, Jakobsen BK (2012) Monoclonal TCR-redirected tumor cell killing. Nat Med 18(6):980–987PubMedCrossRefGoogle Scholar
  204. 204.
    Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, June CH (2015) NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21(8):914–921.  https://doi.org/10.1038/nm.3910CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Kang S, Li Y, Bao Y, Li Y (2019) High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells. Front Med 13(1):69–82.  https://doi.org/10.1007/s11684-018-0677-1CrossRefPubMedGoogle Scholar
  206. 206.
    Matsuda T, Leisegang M, Park J-H, Ren L, Kato T, Ikeda Y, Harada M, Kiyotani K, Lengyel E, Fleming GF, Nakamura Y (2018) Induction of neoantigen-specific cytotoxic T cells and construction of T-cell receptor-engineered T cells for ovarian cancer. Clin Cancer Res 24(21):5357–5367PubMedCrossRefGoogle Scholar
  207. 207.
    Kato T, Matsuda T, Ikeda Y, Park J-H, Leisegang M, Yoshimura S, Hikichi T, Harada M, Zewde M, Sato S, Hasegawa K, Kiyotani K, Nakamura Y (2018) Effective screening of T cells recognizing neoantigens and construction of T-cell receptor-engineered T cells. Oncotarget 9(13):11009–11019PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 86(24):10024–10028PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Duan H, Huang H, Jing G (2019) An antibody Fab fragment-based chimeric antigen receptor could efficiently eliminate human thyroid cancer cells. J Cancer 10(8):1890–1895.  https://doi.org/10.7150/jca.30163CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Gross G, Eshhar Z (2016) Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol 56:59–83PubMedCrossRefGoogle Scholar
  211. 211.
    Ramos CA, Dotti G (2011) Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther 11(7):855–873.  https://doi.org/10.1517/14712598.2011.573476CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR, Schulman A, Du J, Wang F, Singer O, Ma J, Nunez V, Shen J, Woods AK, Wright TM, Schultz PG, Kim CH, Young TS (2016) Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci U S A 113(4):E459–E468.  https://doi.org/10.1073/pnas.1524155113CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Romeo C, Marine A, Seed B (1992) Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor zeta chain. Cell 68:889–897PubMedCrossRefGoogle Scholar
  214. 214.
    Lim WA, June CH (2017) The principles of engineering immune cells to treat cancer. Cell 168(4):724–740.  https://doi.org/10.1016/j.cell.2017.01.016CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Dodson LF, Boomer JS, Deppong CM, Shah DD, Sim J, Bricker TL, Russell JH, Green JM (2009) Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation. Mol Cell Biol 29(13):3710–3721.  https://doi.org/10.1128/MCB.01869-08CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Boomer JS, Green JM (2010) An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol 2(8):a002436.  https://doi.org/10.1101/cshperspect.a002436CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Wu LX, La Rose J, Chen L, Neale C, Mak T, Okkenhaug K, Wange R, Rottapel R (2005) CD28 regulates the translation of Bcl-xL via the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway. J Immunol 174(1):180–194.  https://doi.org/10.4049/jimmunol.174.1.180CrossRefPubMedGoogle Scholar
  218. 218.
    Zapata JM, Perez-Chacon G, Carr-Baena P, Martinez-Forero I, Azpilikueta A, Otano I, Melero I (2018) CD137 (4-1BB) signalosome: complexity is a matter of TRAFs. Front Immunol 9:2618.  https://doi.org/10.3389/fimmu.2018.02618CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Nam KO, Kang H, Shin SM, Cho KH, Kwon B, Kwon BS, Kim SJ, Lee HW (2005) Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes. J Immunol 174(4):1898–1905.  https://doi.org/10.4049/jimmunol.174.4.1898CrossRefPubMedGoogle Scholar
  220. 220.
    Abate-Daga D, Davila ML (2016) CAR models: next-generation CAR modifications for enhanced T-cell function. Mol Ther Oncolytics 3:16014.  https://doi.org/10.1038/mto.2016.14CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Guedan S, Calderon H, Posey AD Jr, Maus MV (2019) Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev 12:145–156.  https://doi.org/10.1016/j.omtm.2018.12.009CrossRefPubMedGoogle Scholar
  222. 222.
    Weinkove R, George P, Dasyam N, McLellan AD (2019) Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunol 8(5):e1049.  https://doi.org/10.1002/cti2.1049CrossRefGoogle Scholar
  223. 223.
    Sadelain M, Brentjens R, Riviere I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3(4):388–398PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Shirasu N, Yamada H, Shibaguchi H, Kuroki M, Kuroki M (2015) Corrigendum to “Molecular characterization of a fully human chimeric T-cell antigen receptor for tumor-associated antigen EpCAM”. Biomed Res Int 2015:292436PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Kalaitsidou M, Kueberuwa G, Schutt A, Gilham DE (2015) CAR T-cell therapy: toxicity and the relevance of preclinical models. Immunotherapy 7(5):487–497PubMedCrossRefGoogle Scholar
  226. 226.
    Hermanson DL, Kaufman DS (2015) Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol 6:195.  https://doi.org/10.3389/fimmu.2015.00195CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Wang D, Aguilar B, Starr R, Alizadeh D, Brito A, Sarkissian A, Ostberg JR, Forman SJ, Brown CE (2018) Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. JCI Insight 3(10).  https://doi.org/10.1172/jci.insight.99048
  228. 228.
    Hong LK, Chen Y, Smith CC, Montgomery SA, Vincent BG, Dotti G, Savoldo B (2018) CD30-redirected chimeric antigen receptor T cells target CD30(+) and CD30(−) embryonal carcinoma via antigen-dependent and Fas/FasL interactions. Cancer Immunol Res 6(10):1274–1287.  https://doi.org/10.1158/2326-6066.CIR-18-0065CrossRefPubMedGoogle Scholar
  229. 229.
    Rabinovich PM, Komarovskaya ME, Wrzesinski SH, Alderman JL, Budak-Alpdogan T, Karpikov A, Guo H, Flavell RA, Cheung NK, Weissman SM, Bahceci E (2009) Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes. Hum Gene Ther 20(1):51–61.  https://doi.org/10.1089/hum.2008.068CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Du Y, Wei Y (2018) Therapeutic potential of natural killer cells in gastric cancer. Front Immunol 9:3095.  https://doi.org/10.3389/fimmu.2018.03095CrossRefPubMedGoogle Scholar
  231. 231.
    Bollino D, Webb TJ (2017) Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl Res 187:32–43.  https://doi.org/10.1016/j.trsl.2017.06.003CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Fisher J, Anderson J (2018) Engineering approaches in human gamma delta T cells for cancer immunotherapy. Front Immunol 9:1409.  https://doi.org/10.3389/fimmu.2018.01409CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Capsomidis A, Benthall G, Van Acker HH, Fisher J, Kramer AM, Abeln Z, Majani Y, Gileadi T, Wallace R, Gustafsson K, Flutter B, Anderson J (2018) Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation. Mol Ther 26(2):354–365.  https://doi.org/10.1016/j.ymthe.2017.12.001CrossRefPubMedGoogle Scholar
  234. 234.
    Kriegsmann K, Kriegsmann M, von Bergwelt-Baildon M, Cremer M, Witzens-Harig M (2018) NKT cells - new players in CAR cell immunotherapy? Eur J Haematol 101(6):750–757.  https://doi.org/10.1111/ejh.13170CrossRefPubMedGoogle Scholar
  235. 235.
    Simon B, Wiesinger M, Marz J, Wistuba-Hamprecht K, Weide B, Schuler-Thurner B, Schuler G, Dorrie J, Uslu U (2018) The generation of CAR-transfected natural killer T cells for the immunotherapy of melanoma. Int J Mol Sci 19(8).  https://doi.org/10.3390/ijms19082365PubMedCentralCrossRefPubMedGoogle Scholar
  236. 236.
    Roberts MR, Cooke KS, Tran AC, Smith KA, Lin WY, Wang M, Dull TJ, Farson D, Zsebo KM, Finer MH (1998) Antigen-specific cytolysis by neutrophils and NK cells expressing chimeric immune receptors bearing zeta or gamma signaling domains. J Immunol 161(1):375–384PubMedGoogle Scholar
  237. 237.
    Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B, Zhou L, Loew A, Young RM, June CH, Zhao Y (2015) Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res 75(17):3596–3607.  https://doi.org/10.1158/0008-5472.CAN-15-0159CrossRefPubMedPubMedCentralGoogle Scholar
  238. 238.
    Park S, Shevlin E, Vedvyas Y, Zaman M, Park S, Hsu YS, Min IM, Jin MM (2017) Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep 7(1):14366.  https://doi.org/10.1038/s41598-017-14749-3CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Drent E, Themeli M, Poels R, de Jong-Korlaar R, Yuan H, de Bruijn J, Martens ACM, Zweegman S, van de Donk N, Groen RWJ, Lokhorst HM, Mutis T (2017) A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther 25(8):1946–1958.  https://doi.org/10.1016/j.ymthe.2017.04.024CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, Rodgers DT, Pugh HM, Singer O, Sun SB, Fonslow BR, Kochenderfer JN, Wright TM, Schultz PG, Young TS, Kim CH, Cao Y (2016) Versatile strategy for controlling the specificity and activity of engineered T cells. Proc Natl Acad Sci U S A 113(4):E450–E458.  https://doi.org/10.1073/pnas.1524193113CrossRefPubMedCentralPubMedGoogle Scholar
  241. 241.
    Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, Guo X, Liu H, Ding N, Zhang T, Duan P, Lin Y, Zheng W, Wang X, Lin N, Tu M, Xie Y, Zhang C, Liu W, Deng L, Gao S, Ping L, Wang X, Zhou N, Zhang J, Wang Y, Lin S, Mamuti M, Yu X, Fang L, Wang S, Song H, Wang G, Jones L, Zhu J, Chen SY (2019) A safe and potent anti-CD19 CAR T cell therapy. Nat Med.  https://doi.org/10.1038/s41591-019-0421-7PubMedCrossRefGoogle Scholar
  242. 242.
    Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, Roszik J, Rabinovich B, Olivares S, Krishnamurthy J, Zhang L, Najjar AM, Huls MH, Lee DA, Champlin RE, Kontoyiannis DP, Cooper LJN (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A 111(29):10660–10665PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Townsend MH, Shrestha G, Robison RA, O’Neill KL (2018) The expansion of targetable biomarkers for CAR T cell therapy. J Exp Clin Cancer Res 37(1):163.  https://doi.org/10.1186/s13046-018-0817-0CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Shaffer DR, Savoldo B, Yi Z, Chow KKH, Kakarla S, Spencer DM, Dotti G, Wu M-F, Liu H, Kenney S, Gottschalk S (2011) T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood 117(16):4304–4314PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Urbanska K, Lanitis E, Poussin M, Lynn RC, Gavin BP, Kelderman S, Yu J, Scholler N, Powell DJ Jr (2012) A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res 72(7):1844–1852PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Liu K, Liu X, Peng Z, Sun H, Zhang M, Zhang J, Liu S, Hao L, Lu G, Zheng K, Gong X, Wu D, Wang F, Shen L (2015) Retargeted human avidin-CAR T cells for adoptive immunotherapy of EGFRvIII expressing gliomas and their evaluation via optical imaging. Oncotarget 6(27):23735–23747PubMedPubMedCentralGoogle Scholar
  247. 247.
    Bridgeman JS, Ladell K, Sheard VE, Miners K, Hawkins RE, Price DA, Gilham DE (2014) CD3zeta-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy. Clin Exp Immunol 175(2):258–267.  https://doi.org/10.1111/cei.12216CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K, Tomita A, Kiyoi H, Nishida T, Naoe T, Murata M (2015) Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8+ T cells. J Immunol 194(3):911–920.  https://doi.org/10.4049/jimmunol.1402346CrossRefPubMedGoogle Scholar
  249. 249.
    Stone JD, Aggen DH, Schietinger A, Schreiber H, Kranz DM (2012) A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs). Oncoimmunology 1(6):863–873.  https://doi.org/10.4161/onci.20592CrossRefPubMedPubMedCentralGoogle Scholar
  250. 250.
    Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, Kaplan RN, Patterson GH, Fry TJ, Orentas RJ, Mackall CL (2015) 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21(6):581–590.  https://doi.org/10.1038/nm.3838CrossRefPubMedPubMedCentralGoogle Scholar
  251. 251.
    Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, Cabral JMS, Rooney CM, Orange JS, Brenner MK, Mamonkin M (2017) Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep 21(1):17–26PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Ajina A, Maher J (2018) Strategies to address chimeric antigen receptor tonic signaling. Mol Cancer Ther 17(9):1795–1815PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Watanabe N, Bajgain P, Sukumaran S, Ansari S, Heslop HE, Rooney CM, Brenner MK, Leen AM, Vera JF (2016) Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology 5(12):e1253656.  https://doi.org/10.1080/2162402X.2016.1253656CrossRefPubMedPubMedCentralGoogle Scholar
  254. 254.
    Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M (2019) Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med 25(1):82–88.  https://doi.org/10.1038/s41591-018-0290-5CrossRefPubMedGoogle Scholar
  255. 255.
    Tschumi BO, Dumauthioz N, Marti B, Zhang L, Schneider P, Mach JP, Romero P, Donda A (2018) CART cells are prone to Fas- and DR5-mediated cell death. J Immunother Cancer 6(1):71.  https://doi.org/10.1186/s40425-018-0385-zCrossRefPubMedPubMedCentralGoogle Scholar
  256. 256.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518.  https://doi.org/10.1056/NEJMoa1215134CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, Barrett DM, Weiss SL, Fitzgerald JC, Berg RA, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White JC, Nazimuddin F, Wertheim G, Levine BL, June CH, Porter DL, Grupp SA (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 6(6):664–679PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Uttenthal BJ, Chua I, Morris EC, Stauss HJ (2012) Challenges in T cell receptor gene therapy. J Gene Med 14(6):386–399PubMedCrossRefPubMedCentralGoogle Scholar
  260. 260.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528PubMedCrossRefPubMedCentralGoogle Scholar
  261. 261.
    Evans AG, Rothberg PG, Burack WR, Huntington SF, Porter DL, Friedberg JW, Liesveld JL (2015) Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells. Br J Haematol 171(2):205–209PubMedCrossRefPubMedCentralGoogle Scholar
  262. 262.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Cho JH, Collins JJ, Wong WW (2018) Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173(6):1426–1438.e1411.  https://doi.org/10.1016/j.cell.2018.03.038CrossRefPubMedPubMedCentralGoogle Scholar
  264. 264.
    Walseng E, Koksal H, Sektioglu IM, Fane A, Skorstad G, Kvalheim G, Gaudernack G, Inderberg EM, Walchli S (2017) A TCR-based chimeric antigen receptor. Sci Rep 7(1):10713.  https://doi.org/10.1038/s41598-017-11126-yCrossRefPubMedPubMedCentralGoogle Scholar
  265. 265.
    Helsen CW, Hammill JA, Lau VWC, Mwawasi KA, Afsahi A, Bezverbnaya K, Newhook L, Hayes DL, Aarts C, Bojovic B, Denisova GF, Kwiecien JM, Brain I, Derocher H, Milne K, Nelson BH, Bramson JL (2018) The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun 9(1):3049PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Baeuerle PA, Ding J, Patel E, Thorausch N, Horton H, Gierut J, Scarfo I, Choudhary R, Kiner O, Krishnamurthy J, Le B, Morath A, Baldeviano GC, Quinn J, Tavares P, Wei Q, Weiler S, Maus MV, Getts D, Schamel WW, Hofmeister R (2019) Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat Commun 10(1):2087.  https://doi.org/10.1038/s41467-019-10097-0CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    DeFord-Watts LM, Young JA, Pitcher LA, van Oers NSC (2007) The membrane-proximal portion of CD3 epsilon associates with the serine/threonine kinase GRK2. J Biol Chem 282(22):16126–16134PubMedCrossRefGoogle Scholar
  268. 268.
    Yamazaki T, Hamano Y, Tashiro H, Itoh K, Nakano H, Miyatake S, Saito T (1999) CAST, a novel CD3epsilon-binding protein transducing activation signal for interleukin-2 production in T cells. J Biol Chem 274(26):18173–18180PubMedCrossRefGoogle Scholar
  269. 269.
    Deford-Watts LM, Tassin TC, Becker AM, Medeiros JJ, Albanesi JP, Love PE, Wulfing C, van Oers NSC (2009) The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions. J Immunol 183(2):1055–1064PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, Butler MO, Minden MD, Hirano N (2018) A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med 24(3):352–359.  https://doi.org/10.1038/nm.4478CrossRefPubMedPubMedCentralGoogle Scholar
  271. 271.
    Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA (2016) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164(4):770–779PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Shah NN, Maatman T, Hari P, Johnson B (2019) Multi targeted CAR-T cell therapies for B-cell malignancies. Front Oncol 9:146.  https://doi.org/10.3389/fonc.2019.00146CrossRefPubMedPubMedCentralGoogle Scholar
  273. 273.
    D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M (2018) CAR-T cells: the long and winding road to solid tumors. Cell Death Dis 9(3):282.  https://doi.org/10.1038/s41419-018-0278-6CrossRefPubMedPubMedCentralGoogle Scholar
  274. 274.
    Bagashev A, Sotillo E, Tang C-HA, Black KL, Perazzelli J, Seeholzer SH, Argon Y, Barrett DM, Grupp SA, Hu C-CA, Thomas-Tikhonenko A (2018) CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol Cell Biol 38(21):e00383–e00318PubMedPubMedCentralCrossRefGoogle Scholar
  275. 275.
    Schneider D, Xiong Y, Wu D, Nölle V, Schmitz S, Haso W, Kaiser A, Dropulic B, Orentas RJ (2017) A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer 5:42Google Scholar
  276. 276.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K, Bielamowicz K, Chow KK, Brawley VS, Byrd TT, Krebs S, Gottschalk S, Wels WS, Baker ML, Dotti G, Mamonkin M, Brenner MK, Orange JS, Ahmed N (2016) Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Invest 126(8):3036–3052.  https://doi.org/10.1172/JCI83416CrossRefPubMedPubMedCentralGoogle Scholar
  277. 277.
    Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M (2013) Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 31(1):71–75PubMedCrossRefPubMedCentralGoogle Scholar
  278. 278.
    Fedorov VD, Themeli M, Sadelain M (2013) PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med 5(215):215ra172.  https://doi.org/10.1126/scitranslmed.3006597CrossRefPubMedPubMedCentralGoogle Scholar
  279. 279.
    Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, Newick K, Lo A, June CH, Zhao Y, Moon EK (2016) A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res 76(6):1578–1590PubMedPubMedCentralCrossRefGoogle Scholar
  280. 280.
    Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ (2013) Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J Immunol 191(8):4121–4129PubMedCrossRefPubMedCentralGoogle Scholar
  281. 281.
    Kobold S, Grassmann S, Chaloupka M, Lampert C, Wenk S, Kraus F, Rapp M, Duwell P, Zeng Y, Schmollinger JC, Schnurr M, Endres S, RothenfuSser S (2015) Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J Natl Cancer Inst 107(8):djv146PubMedPubMedCentralCrossRefGoogle Scholar
  282. 282.
    Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC (2012) Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol Immunol 51(3–4):263–272.  https://doi.org/10.1016/j.molimm.2012.03.023CrossRefPubMedPubMedCentralGoogle Scholar
  283. 283.
    Chmielewski M, Abken H (2015) TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther 15(8):1145–1154.  https://doi.org/10.1517/14712598.2015.1046430CrossRefPubMedPubMedCentralGoogle Scholar
  284. 284.
    Chmielewski M, Kopecky C, Hombach AA, Abken H (2011) IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res 71(17):5697–5706PubMedCrossRefPubMedCentralGoogle Scholar
  285. 285.
    Yeku OO, Brentjens RJ (2016) Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans 44(2):412–418PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Avanzi MP, Yeku O, Li X, Wijewarnasuriya DP, van Leeuwen DG, Cheung K, Park H, Purdon TJ, Daniyan AF, Spitzer MH, Brentjens RJ (2018) Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep 23(7):2130–2141PubMedPubMedCentralCrossRefGoogle Scholar
  287. 287.
    Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K (2018) IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 36(4):346–351.  https://doi.org/10.1038/nbt.4086CrossRefPubMedPubMedCentralGoogle Scholar
  288. 288.
    Shum T, Kruse RL, Rooney CM (2018) Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities. Expert Opin Biol Ther 18(6):653–664PubMedPubMedCentralCrossRefGoogle Scholar
  289. 289.
    Curran KJ, Seinstra BA, Nikhamin Y, Yeh R, Usachenko Y, van Leeuwen DG, Purdon T, Pegram HJ, Brentjens RJ (2015) Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther 23(4):769–778PubMedPubMedCentralCrossRefGoogle Scholar
  290. 290.
    Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, Song M, Miele MM, Li Z, Wang P, Yan S, Xiang J, Ma X, Seshan VE, Hendrickson RC, Liu C, Brentjens RJ (2018) Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36(9):847–856PubMedPubMedCentralCrossRefGoogle Scholar
  291. 291.
    Di Stasi A, Tey S-K, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 365(18):1673–1683PubMedPubMedCentralCrossRefGoogle Scholar
  292. 292.
    Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, McNally KA, Lim WA (2016) Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167(2):419–432.e416PubMedPubMedCentralCrossRefGoogle Scholar
  293. 293.
    Kamiya T, Wong D, Png YT, Campana D (2018) A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. Blood Adv 2(5):517–528PubMedPubMedCentralCrossRefGoogle Scholar
  294. 294.
    Legrand F, Driss V, Woerly G, Loiseau S, Hermann E, Fournie JJ, Heliot L, Mattot V, Soncin F, Gougeon ML, Dombrowicz D, Capron M (2009) A functional gammadeltaTCR/CD3 complex distinct from gammadeltaT cells is expressed by human eosinophils. PLoS One 4(6):e5926.  https://doi.org/10.1371/journal.pone.0005926CrossRefPubMedCentralGoogle Scholar
  295. 295.
    Beham AW, Puellmann K, Laird R, Fuchs T, Streich R, Breysach C, Raddatz D, Oniga S, Peccerella T, Findeisen P, Kzhyshkowska J, Gratchev A, Schweyer S, Saunders B, Wessels JT, Mobius W, Keane J, Becker H, Ganser A, Neumaier M, Kaminski WE (2011) A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis. PLoS Pathog 7(11):e1002375.  https://doi.org/10.1371/journal.ppat.1002375CrossRefPubMedPubMedCentralGoogle Scholar
  296. 296.
    Kaminski WE, Beham AW, Kzhyshkowska J, Gratchev A, Puellmann K (2013) On the horizon: flexible immune recognition outside lymphocytes. Immunobiology 218(3):418–426.  https://doi.org/10.1016/j.imbio.2012.05.024CrossRefPubMedPubMedCentralGoogle Scholar
  297. 297.
    Mensali N, Dillard P, Hebeisen M, Lorenz S, Theodossiou T, Myhre MR, Fane A, Gaudernack G, Kvalheim G, Myklebust JH, Inderberg EM, Walchli S (2019) NK cells specifically TCR-dressed to kill cancer cells. EBioMedicine 40:106–117.  https://doi.org/10.1016/j.ebiom.2019.01.031CrossRefPubMedPubMedCentralGoogle Scholar
  298. 298.
    Hu W, Wang G, Huang D, Sui M, Xu Y (2019) Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front Immunol 10:1205PubMedPubMedCentralCrossRefGoogle Scholar
  299. 299.
    Heczey A, Liu D, Tian G, Courtney AN, Wei J, Marinova E, Gao X, Guo L, Yvon E, Hicks J, Liu H, Dotti G, Metelitsa LS (2014) Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 124(18):2824–2833.  https://doi.org/10.1182/blood-2013-11-541235CrossRefPubMedPubMedCentralGoogle Scholar
  300. 300.
    Tosolini M, Pont F, Poupot M, Vergez F, Nicolau-Travers ML, Vermijlen D, Sarry JE, Dieli F, Fournie JJ (2017) Assessment of tumor-infiltrating TCRVgamma9Vdelta2 gammadelta lymphocyte abundance by deconvolution of human cancers microarrays. Oncoimmunology 6(3):e1284723.  https://doi.org/10.1080/2162402X.2017.1284723CrossRefPubMedCentralPubMedGoogle Scholar
  301. 301.
    Deniger DC, Moyes JS, Cooper LJ (2014) Clinical applications of gamma delta T cells with multivalent immunity. Front Immunol 5:636.  https://doi.org/10.3389/fimmu.2014.00636CrossRefPubMedPubMedCentralGoogle Scholar
  302. 302.
    Morita CT, Jin C, Sarikonda G, Wang H (2007) Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev 215:59–76PubMedCrossRefGoogle Scholar
  303. 303.
    Wu YL, Ding YP, Tanaka Y, Shen LW, Wei CH, Minato N, Zhang W (2014) gammadelta T cells and their potential for immunotherapy. Int J Biol Sci 10(2):119–135.  https://doi.org/10.7150/ijbs.7823CrossRefPubMedPubMedCentralGoogle Scholar
  304. 304.
    Caccamo N, Todaro M, Sireci G, Meraviglia S, Stassi G, Dieli F (2013) Mechanisms underlying lineage commitment and plasticity of human gammadelta T cells. Cell Mol Immunol 10(1):30–34.  https://doi.org/10.1038/cmi.2012.42CrossRefPubMedGoogle Scholar
  305. 305.
    Cordova A, Toia F, La Mendola C, Orlando V, Meraviglia S, Rinaldi G, Todaro M, Cicero G, Zichichi L, Donni PL, Caccamo N, Stassi G, Dieli F, Moschella F (2012) Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS One 7(11):e49878.  https://doi.org/10.1371/journal.pone.0049878CrossRefPubMedPubMedCentralGoogle Scholar
  306. 306.
    Pauza CD, Liou ML, Lahusen T, Xiao L, Lapidus RG, Cairo C, Li H (2018) Gamma delta T cell therapy for cancer: it is good to be local. Front Immunol 9:1305.  https://doi.org/10.3389/fimmu.2018.01305CrossRefPubMedPubMedCentralGoogle Scholar
  307. 307.
    Sheridan BS, Romagnoli PA, Pham QM, Fu HH, Alonzo F III, Schubert WD, Freitag NE, Lefrancois L (2013) gammadelta T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39(1):184–195.  https://doi.org/10.1016/j.immuni.2013.06.015CrossRefPubMedPubMedCentralGoogle Scholar
  308. 308.
    Zhao Y, Niu C, Cui J (2018) Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J Transl Med 16(1):3.  https://doi.org/10.1186/s12967-017-1378-2CrossRefPubMedPubMedCentralGoogle Scholar
  309. 309.
    Lawand M, Dechanet-Merville J, Dieu-Nosjean MC (2017) Key features of gamma-delta T-cell subsets in human diseases and their immunotherapeutic implications. Front Immunol 8:761.  https://doi.org/10.3389/fimmu.2017.00761CrossRefPubMedPubMedCentralGoogle Scholar
  310. 310.
    Handgretinger R, Schilbach K (2018) The potential role of gammadelta T cells after allogeneic HCT for leukemia. Blood 131(10):1063–1072.  https://doi.org/10.1182/blood-2017-08-752162CrossRefPubMedGoogle Scholar
  311. 311.
    van der Veken LT, Coccoris M, Swart E, Falkenburg JH, Schumacher TN, Heemskerk MH (2009) Alpha beta T cell receptor transfer to gamma delta T cells generates functional effector cells without mixed TCR dimers in vivo. J Immunol 182(1):164–170.  https://doi.org/10.4049/jimmunol.182.1.164CrossRefPubMedGoogle Scholar
  312. 312.
    Hiasa A, Nishikawa H, Hirayama M, Kitano S, Okamoto S, Chono H, Yu SS, Mineno J, Tanaka Y, Minato N, Kato I, Shiku H (2009) Rapid alphabeta TCR-mediated responses in gammadelta T cells transduced with cancer-specific TCR genes. Gene Ther 16(5):620–628.  https://doi.org/10.1038/gt.2009.6CrossRefPubMedGoogle Scholar
  313. 313.
    Rischer M, Pscherer S, Duwe S, Vormoor J, Jurgens H, Rossig C (2004) Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br J Haematol 126(4):583–592PubMedCrossRefGoogle Scholar
  314. 314.
    Deniger DC, Switzer K, Mi T, Maiti S, Hurton L, Singh H, Huls H, Olivares S, Lee DA, Champlin RE, Cooper LJ (2013) Bispecific T-cells expressing polyclonal repertoire of endogenous gammadelta T-cell receptors and introduced CD19-specific chimeric antigen receptor. Mol Ther 21(3):638–647.  https://doi.org/10.1038/mt.2012.267CrossRefPubMedPubMedCentralGoogle Scholar
  315. 315.
    Fisher J, Abramowski P, Wisidagamage Don ND, Flutter B, Capsomidis A, Cheung GW, Gustafsson K, Anderson J (2017) Avoidance of on-target off-tumor activation using a co-stimulation-only chimeric antigen receptor. Mol Ther 25(5):1234–1247.  https://doi.org/10.1016/j.ymthe.2017.03.002CrossRefPubMedPubMedCentralGoogle Scholar
  316. 316.
    van Willigen WW, Bloemendal M, Gerritsen WR, Schreibelt G, de Vries IJM, Bol KF (2018) Dendritic cell cancer therapy: vaccinating the right patient at the right time. Front Immunol 9:2265.  https://doi.org/10.3389/fimmu.2018.02265CrossRefPubMedPubMedCentralGoogle Scholar
  317. 317.
    Braza MS, Klein B (2013) Anti-tumour immunotherapy with Vgamma9Vdelta2 T lymphocytes: from the bench to the bedside. Br J Haematol 160(2):123–132PubMedCrossRefGoogle Scholar
  318. 318.
    Hotblack A, Holler A, Piapi A, Ward S, Stauss HJ, Bennett CL (2018) Tumor-resident dendritic cells and macrophages modulate the accumulation of TCR-engineered T cells in melanoma. Mol Ther 26(6):1471–1481.  https://doi.org/10.1016/j.ymthe.2018.03.011CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of PathologyYale School of MedicineNew HavenUSA

Personalised recommendations