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Homing Improvement: Boosting T Cell Trafficking for Cancer Immunotherapy

  • Joseph M. CantorEmail author
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 9)

Abstract

Advances in T cell tumor immunotherapy have raised hopes for this approach to become a significant treatment for a variety of cancers. Recent successes in leukemia using CAR-modified T cells and in metastatic melanoma using tumor-infiltrating lymphocytes have provided impetus to expand adoptive cellular immunotherapy into treatment of solid tumors. In this setting, adoptively-transferred T cells face a hostile tumor environment that suppresses their anti-tumor functions. In addition, T cells activated and expanded outside of the lymph node lack naturally imprinted homing cues and often exhibit poor homing to most sites of tumor growth. This significant problem has limited the application of cellular tumor immunotherapy to a select few malignancies. However, new ideas to improve the migration of transferred T cells have been generated and tested in preclinical models. Super-charging inflammatory migration of T cells is possible by modulating any number of components in the leukocyte migration machinery, from chemo-attractants, to integrins, to extracellular matrix adhesion ligands. Promising results suggest that the homing problem can indeed be overcome to remove a major barrier in allowing cellular tumor immunotherapy to achieve its full potential as a cancer treatment.

Keywords

T cell Immunotherapy Homing Trafficking Integrin Chemokine Migration 

Abbreviations

ACT

Adoptive cellular tumor immunotherapy

AML

Acute myeloid leukemia

CAR

Chimeric antigen receptor

CCR9

Chemokine receptor 9

CML

Chronic myeloid leukemia

CRISPR

Clustered regularly-interspaced short palindromic repeats

CTLA-4

Cytotoxic T lymphocyte-associated protein 4

DC

Dendritic cell

EGFR

Epidermal growth factor receptor

FAK

Focal adhesion kinase

ICAM-1

Intercellular adhesion molecule 1

IL-1β

Interleukin 1 beta

IL-2

Interleukin 2

IL-6

Interleukin 6

IVIG

Intravenous immunoglobulin

LFA-1

Leukocyte functional adhesion molecule 1

NK

Natural killer cell

PD-1

Programmed cell death protein 1

PKA-I

Protein kinase A, Type I

SDF-1α

Stem cell-derived factor 1 alpha

TAA

Tumor-associated antigen(s)

TCM

Central memory T cell

TCR

T cell receptor

TEM

Effector memory T cell

TIL(s)

Tumor-infiltrating lymphocyte(s)

TLS

Tumor lysis syndrome

TNF-α

Tumor necrosis factor-alpha

TSA

Tumor-specific antigen(s)

VCAM-1

Vascular cell adhesion molecule 1

VEGFR

Vascular endothelial growth factor receptor

VLA-4

Very late activation antigen 4

Notes

Acknowledgements

The author would like to thank Dr. Mark H. Ginsberg and Dr. David M. Rose for their contributions to the integrin transregulation studies.

No potential conflicts of interest were disclosed.

References

  1. 1.
    Miller JF, Sadelain M. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell. 2015;27(4):439–49. doi: 10.1016/j.ccell.2015.03.007.PubMedCrossRefGoogle Scholar
  2. 2.
    Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14. doi: 10.1016/j.cell.2015.03.030.PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62–8. doi: 10.1126/science.aaa4967.PubMedCrossRefGoogle Scholar
  4. 4.
    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. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–28. doi: 10.1016/S0140-6736(14)61403-3.PubMedCrossRefGoogle Scholar
  5. 5.
    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. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. doi: 10.1056/NEJMoa1407222.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2014;257(1):56–71. doi: 10.1111/imr.12132.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39(1):49–60. doi: 10.1016/j.immuni.2013.07.002.PubMedCrossRefGoogle Scholar
  8. 8.
    Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Science Transl Med. 2012;4(127):127–8. doi: 10.1126/scitranslmed.3003634.CrossRefGoogle Scholar
  9. 9.
    Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12(4):265–77. doi: 10.1038/nrc3258.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Minagawa K, Zhou X, Mineishi S, Di Stasi A. Seatbelts in CAR therapy: how safe are CARS? Pharmaceuticals (Basel). 2015;8(2):230–49. doi: 10.3390/ph8020230.CrossRefGoogle Scholar
  11. 11.
    Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6, e1792. doi: 10.1038/cddis.2015.162.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Abken H. Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors. Immunotherapy. 2015;7(5):535–44. doi: 10.2217/imt.15.15.PubMedCrossRefGoogle Scholar
  13. 13.
    Bellone M, Calcinotto A, Corti A. Won’t you come on in? How to favor lymphocyte infiltration in tumors. Oncoimmunology. 2012;1(6):986–8. doi: 10.4161/onci.20213.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Fisher DT, Chen Q, Appenheimer MM, Skitzki J, Wang WC, Odunsi K, Evans SS. Hurdles to lymphocyte trafficking in the tumor microenvironment: implications for effective immunotherapy. Immunol Invest. 2006;35(3–4):251–77. doi: 10.1080/08820130600745430.PubMedCrossRefGoogle Scholar
  15. 15.
    Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. doi: 10.1038/nrc3236.PubMedCrossRefGoogle Scholar
  16. 16.
    Redman JM, Hill EM, AlDeghaither D, Weiner LM. Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol. 2015;67:28–45. doi: 10.1016/j.molimm.2015.04.002.PubMedCrossRefGoogle Scholar
  17. 17.
    Lim SH, Levy R. Translational medicine in action: anti-CD20 therapy in lymphoma. J Immunol. 2014;193(4):1519–24. doi: 10.4049/jimmunol.1490027.PubMedCrossRefGoogle Scholar
  18. 18.
    Hayes GM, Chinn L, Cantor JM, Cairns B, Levashova Z, Tran H, Velilla T, Duey D, Lippincott J, Zachwieja J, Ginsberg MH, HvdH E. Antitumor activity of an anti-CD98 antibody. Int J Cancer. 2015;137(3):710–20. doi: 10.1002/ijc.29415.PubMedCrossRefGoogle Scholar
  19. 19.
    Pentcheva-Hoang T, Corse E, Allison JP. Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections. Immunol Rev. 2009;229(1):67–87. doi: 10.1111/j.1600-065X.2009.00763.x.PubMedCrossRefGoogle Scholar
  20. 20.
    Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265–76. doi: 10.1016/j.it.2015.02.008.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Mittal R, Chen CW, Lyons JD, Margoles LM, Liang Z, Coopersmith CM, Ford ML. Murine lung cancer induces generalized T-cell exhaustion. J Surg Res. 2015;195(2):541–9. doi: 10.1016/j.jss.2015.02.004.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61. doi: 10.1126/science.aaa8172.PubMedCrossRefGoogle Scholar
  23. 23.
    Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20(2):241–6. doi: 10.1016/j.coi.2008.04.008.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? Lancet Oncol. 2012;13(1):e32–42. doi: 10.1016/S1470-2045(11)70155-3.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang Y, Gallastegui N, Rosenblatt JD. Regulatory B cells in anti-tumor immunity. Int Immunol. 2015;27:521–30. doi: 10.1093/intimm/dxv034.PubMedCrossRefGoogle Scholar
  26. 26.
    Fournier P, Schirrmacher V. Bispecific antibodies and trispecific immunocytokines for targeting the immune system against cancer: preparing for the future. BioDrugs. 2013;27(1):35–53. doi: 10.1007/s40259-012-0008-z.PubMedCrossRefGoogle Scholar
  27. 27.
    Hoffman LM, Gore L. Blinatumomab, a bi-specific anti-CD19/CD3 BiTE((R)) antibody for the treatment of acute lymphoblastic leukemia: perspectives and current pediatric applications. Front Oncol. 2014;4:63. doi: 10.3389/fonc.2014.00063.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67. doi: 10.1016/S1470-2045(13)70585-0.PubMedCrossRefGoogle Scholar
  29. 29.
    Butterfield LH. Dendritic cells in cancer immunotherapy clinical trials: are we making progress? Front Immunol. 2013;4:454. doi: 10.3389/fimmu.2013.00454.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Cohn L, Delamarre L. Dendritic cell-targeted vaccines. Front Immunol. 2014;5:255. doi: 10.3389/fimmu.2014.00255.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Pizzurro GA, Barrio MM. Dendritic cell-based vaccine efficacy: aiming for hot spots. Front Immunol. 2015;6:91. doi: 10.3389/fimmu.2015.00091.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Graff JN, Chamberlain ED. Sipuleucel-T in the treatment of prostate cancer: an evidence-based review of its place in therapy. Core Evidence. 2015;10:1–10. doi: 10.2147/CE.S54712.PubMedGoogle Scholar
  33. 33.
    Yang B, Jeang J, Yang A, Wu TC, Hung CF. DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother. 2014;10(11):3153–64. doi: 10.4161/21645515.2014.980686.PubMedCrossRefGoogle Scholar
  34. 34.
    Liao S, Zhang W, Hu X, Wang W, Deng D, Wang H, Wang C, Zhou J, Wang S, Zhang H, Ma D. A novel “priming-boosting” strategy for immune interventions in cervical cancer. Mol Immunol. 2015;64(2):295–305. doi: 10.1016/j.molimm.2014.12.007.PubMedCrossRefGoogle Scholar
  35. 35.
    Fend L, Gatard-Scheikl T, Kintz J, Gantzer M, Schaedler E, Rittner K, Cochin S, Fournel S, Preville X. Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control tumor growth upon combinatorial treatment with a TLR9 agonist. Cancer Immunol Res. 2014;2(12):1163–74. doi: 10.1158/2326-6066.CIR-14-0050.PubMedCrossRefGoogle Scholar
  36. 36.
    Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–8. doi: 10.4049/jimmunol.1490019.PubMedCrossRefGoogle Scholar
  37. 37.
    Ramos CA, Dotti G. Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther. 2011;11(7):855–73. doi: 10.1517/14712598.2011.573476.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625–35. doi: 10.1182/blood-2013-11-492231.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15(8):1145–54. doi: 10.1517/14712598.2015.1046430.PubMedCrossRefGoogle Scholar
  40. 40.
    Pegram HJ, Park JH, Brentjens RJ. CD28z CARs and armored CARs. Cancer J. 2014;20(2):127–33. doi: 10.1097/PPO.0000000000000034.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388–98. doi: 10.1158/2159-8290.CD-12-0548.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Srivastava S, Riddell SR. Engineering CAR-T cells: design concepts. Trends Immunol. 2015;36:494–502. doi: 10.1016/j.it.2015.06.004.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, Kalos M, Riley JL, Deeks SG, Mitsuyasu RT, Bernstein WB, Aronson NE, Levine BL, Bushman FD, June CH. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4(132):132ra153. doi: 10.1126/scitranslmed.3003761.CrossRefGoogle Scholar
  44. 44.
    Gilham DE, Debets R, Pule M, Hawkins RE, Abken H. CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med. 2012;18(7):377–84. doi: 10.1016/j.molmed.2012.04.009.PubMedCrossRefGoogle Scholar
  45. 45.
    Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–28. doi: 10.1182/blood-2011-04-348540.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi: 10.1126/scitranslmed.3002842.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi: 10.1056/NEJMoa1103849.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Xu XJ, Zhao HZ, Tang YM. Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials. Leuk Lymphoma. 2013;54(2):255–60. doi: 10.3109/10428194.2012.715350.PubMedCrossRefGoogle Scholar
  49. 49.
    Maus MV, Kovacs B, Kwok WW, Nepom GT, Schlienger K, Riley JL, Allman D, Finkel TH, June CH. Extensive replicative capacity of human central memory T cells. J Immunol. 2004;172(11):6675–83.PubMedCrossRefGoogle Scholar
  50. 50.
    Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest. 2008;118(1):294–305. doi: 10.1172/JCI32103.PubMedCrossRefGoogle Scholar
  51. 51.
    Barrett DM, Grupp SA, June CH. Chimeric antigen receptor- and TCR-modified T cells enter main street and wall street. J Immunol. 2015;195(3):755–61. doi: 10.4049/jimmunol.1500751.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Davila ML, Bouhassira DC, Park JH, Curran KJ, Smith EL, Pegram HJ, Brentjens R. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol. 2014;99(4):361–71. doi: 10.1007/s12185-013-1479-5.PubMedCrossRefGoogle Scholar
  53. 53.
    Klingemann H. Are natural killer cells superior CAR drivers? Oncoimmunology. 2014;3, e28147. doi: 10.4161/onci.28147.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95. doi: 10.1182/blood-2014-05-552729.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–22. doi: 10.1097/PPO.0000000000000035.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol. 2015;16(8):850–8. doi: 10.1038/ni.3201.PubMedCrossRefGoogle Scholar
  57. 57.
    Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizee G, Radvanyi L, Hwu P. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 2012;72(20):5209–18. doi: 10.1158/0008-5472.CAN-12-1187.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wang L, Amoozgar Z, Huang J, Saleh MH, Xing D, Orsulic S, Goldberg MS. Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol Res. 2015;3(9):1030–41. doi: 10.1158/2326-6066.CIR-15-0073.PubMedCrossRefGoogle Scholar
  59. 59.
    Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, Corti A, Bellone M. Targeting TNF-alpha to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J Immunol. 2012;188(6):2687–94. doi: 10.4049/jimmunol.1101877.PubMedCrossRefGoogle Scholar
  60. 60.
    Chen Q, Fisher DT, Clancy KA, Gauguet JM, Wang WC, Unger E, Rose-John S, von Andrian UH, Baumann H, Evans SS. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol. 2006;7(12):1299–308. doi: 10.1038/ni1406.PubMedCrossRefGoogle Scholar
  61. 61.
    Mikucki ME, Fisher DT, Ku AW, Appenheimer MM, Muhitch JB, Evans SS. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int J Hyperthermia. 2013;29(5):464–73. doi: 10.3109/02656736.2013.807440.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, Rose-John S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest. 2011;121(10):3846–59. doi: 10.1172/JCI44952.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Vanpouille-Box C, Pilones KA, Wennerberg E, Formenti SC, Demaria S. In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine. 2015;33(51):7415–22. doi: 10.1016/j.vaccine.2015.05.105.PubMedCrossRefGoogle Scholar
  64. 64.
    Zheng Y, Dou Y, Duan L, Cong C, Gao A, Lai Q, Sun Y. Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer. Cell Immunol. 2015;294(1):54–9. doi: 10.1016/j.cellimm.2015.02.003.PubMedCrossRefGoogle Scholar
  65. 65.
    Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, Bouchier-Hayes L, Savoldo B, Dotti G. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 2014;74(18):5195–205. doi: 10.1158/0008-5472.CAN-14-0697.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Brown CE, Vishwanath RP, Aguilar B, Starr R, Najbauer J, Aboody KS, Jensen MC. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol. 2007;179(5):3332–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM, Wang E, Young HA, Murphy PM, Hwu P. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther. 2002;13(16):1971–80. doi: 10.1089/10430340260355374.PubMedCrossRefGoogle Scholar
  68. 68.
    Asai H, Fujiwara H, An J, Ochi T, Miyazaki Y, Nagai K, Okamoto S, Mineno J, Kuzushima K, Shiku H, Inoue H, Yasukawa M. Co-introduced functional CCR2 potentiates in vivo anti-lung cancer functionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor. PLoS One. 2013;8(2), e56820. doi: 10.1371/journal.pone.0056820.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, Foster AE. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother. 2010;33(8):780–8. doi: 10.1097/CJI.0b013e3181ee6675.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–402. doi: 10.1182/blood-2009-03-209650.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, Powell Jr DJ, Riley JL, June CH, Albelda SM. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res. 2011;17(14):4719–30. doi: 10.1158/1078-0432.CCR-11-0351.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Cantor JM, Rose DM, Slepak M, Ginsberg MH. Fine-tuning tumor immunity with integrin trans-regulation. Cancer Immunol Res. 2015;3(6):661–7. doi: 10.1158/2326-6066.CIR-13-0226.PubMedCrossRefGoogle Scholar
  73. 73.
    Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525(2):174–81. doi: 10.1016/j.gene.2013.03.098.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med. 2008;205(3):711–23. doi: 10.1084/jem.20071140.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Palmer DC, Chan CC, Gattinoni L, Wrzesinski C, Paulos CM, Hinrichs CS, Powell Jr DJ, Klebanoff CA, Finkelstein SE, Fariss RN, Yu Z, Nussenblatt RB, Rosenberg SA, Restifo NP. Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci U S A. 2008;105(23):8061–6. doi: 10.1073/pnas.0710929105.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. doi: 10.1038/mt.2010.24.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM, Hughes MS, Kammula US, Phan GQ, Lim RM, Wank SA, Restifo NP, Robbins PF, Laurencot CM, Rosenberg SA. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–6. doi: 10.1038/mt.2010.272.PubMedCrossRefGoogle Scholar
  78. 78.
    Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama JW. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013;21(4):904–12. doi: 10.1038/mt.2013.17.PubMedCrossRefGoogle Scholar
  79. 79.
    Xu XJ, Tang YM. Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells. Cancer Lett. 2014;343(2):172–8. doi: 10.1016/j.canlet.2013.10.004.PubMedCrossRefGoogle Scholar
  80. 80.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10. doi: 10.1016/j.immuni.2013.07.012.PubMedCrossRefGoogle Scholar
  81. 81.
    Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39(1):61–73. doi: 10.1016/j.immuni.2013.07.005.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Chmielewski M, Kopecky C, Hombach AA, Abken H. 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. 2011;71(17):5697–706. doi: 10.1158/0008-5472.CAN-11-0103.PubMedCrossRefGoogle Scholar
  83. 83.
    Haanen JB, Thienen H, Blank CU. Toxicity patterns with immunomodulating antibodies and their combinations. Semin Oncol. 2015;42(3):423–8. doi: 10.1053/j.seminoncol.2015.02.011.PubMedCrossRefGoogle Scholar
  84. 84.
    Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85. doi: 10.1158/0008-5472.CAN-08-2281.PubMedCrossRefGoogle Scholar
  85. 85.
    Huang H, Langenkamp E, Georganaki M, Loskog A, Fuchs PF, Dieterich LC, Kreuger J, Dimberg A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kappaB-induced endothelial activation. FASEB J. 2015;29(1):227–38. doi: 10.1096/fj.14-250985.PubMedCrossRefGoogle Scholar
  86. 86.
    Lizee G, Cantu MA, Hwu P. Less yin, more yang: confronting the barriers to cancer immunotherapy. Clin Cancer Res. 2007;13(18 Pt 1):5250–5. doi: 10.1158/1078-0432.CCR-07-1722.PubMedCrossRefGoogle Scholar
  87. 87.
    Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272(5258):60–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Weninger W, Crowley MA, Manjunath N, von Andrian UH. Migratory properties of naive, effector, and memory CD8(+) T cells. J Exp Med. 2001;194(7):953–66.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Masopust D, Schenkel JM. The integration of T cell migration, differentiation and function. Nat Rev Immunol. 2013;13(5):309–20. doi: 10.1038/nri3442.PubMedCrossRefGoogle Scholar
  90. 90.
    Fearon DT. The expansion and maintenance of antigen-selected CD8(+) T cell clones. Adv Immunol. 2007;96:103–39. doi: 10.1016/S0065-2776(07)96003-4.PubMedCrossRefGoogle Scholar
  91. 91.
    von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000;343(14):1020–34. doi: 10.1056/NEJM200010053431407.CrossRefGoogle Scholar
  92. 92.
    Fu H, Wang A, Mauro C, Marelli-Berg F. T lymphocyte trafficking: molecules and mechanisms. Front Biosci (Landmark Ed). 2013;18:422–40.CrossRefGoogle Scholar
  93. 93.
    D’Cruz LM, Rubinstein MP, Goldrath AW. Surviving the crash: transitioning from effector to memory CD8+ T cell. Semin Immunol. 2009;21(2):92–8. doi: 10.1016/j.smim.2009.02.002.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694–707. doi: 10.1016/j.immuni.2014.10.008.PubMedCrossRefGoogle Scholar
  95. 95.
    Rose DM, Alon R, Ginsberg MH. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev. 2007;218:126–34. doi: 10.1111/j.1600-065X.2007.00536.x.PubMedCrossRefGoogle Scholar
  96. 96.
    Alon R, Shulman Z. Chemokine triggered integrin activation and actin remodeling events guiding lymphocyte migration across vascular barriers. Exp Cell Res. 2011;317(5):632–41. doi: 10.1016/j.yexcr.2010.12.007.PubMedCrossRefGoogle Scholar
  97. 97.
    Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, Puzon-McLaughlin W, Lafuente EM, Boussiotis VA, Shattil SJ, Ginsberg MH. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol. 2006;16(18):1796–806. doi: 10.1016/j.cub.2006.08.035.PubMedCrossRefGoogle Scholar
  98. 98.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87.PubMedCrossRefGoogle Scholar
  99. 99.
    Kim C, Ye F, Hu X, Ginsberg MH. Talin activates integrins by altering the topology of the beta transmembrane domain. J Cell Biol. 2012;197(5):605–11. doi: 10.1083/jcb.201112141.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Ye F, Kim C, Ginsberg MH. Reconstruction of integrin activation. Blood. 2012;119(1):26–33. doi: 10.1182/blood-2011-04-292128.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 2010;11(4):288–300. doi: 10.1038/nrm2871.PubMedCentralCrossRefPubMedGoogle Scholar
  102. 102.
    Shen B, Delaney MK, Du X. Inside-out, outside-in, and inside-outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr Opin Cell Biol. 2012;24(5):600–6. doi: 10.1016/j.ceb.2012.08.011.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Zhang Y, Wang H. Integrin signalling and function in immune cells. Immunology. 2012;135(4):268–75. doi: 10.1111/j.1365-2567.2011.03549.x.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Iwamoto DV, Calderwood DA. Regulation of integrin-mediated adhesions. Curr Opin Cell Biol. 2015;36:41–7. doi: 10.1016/j.ceb.2015.06.009.PubMedCrossRefGoogle Scholar
  105. 105.
    Tufail S, Badrealam KF, Sherwani A, Gupta UD, Owais M. Tissue specific heterogeneity in effector immune cell response. Front Immunol. 2013;4:254. doi: 10.3389/fimmu.2013.00254.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Stock A, Napolitani G, Cerundolo V. Intestinal DC in migrational imprinting of immune cells. Immunol Cell Biol. 2013;91(3):240–9. doi: 10.1038/icb.2012.73.PubMedCrossRefGoogle Scholar
  107. 107.
    Mikhak Z, Strassner JP, Luster AD. Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J Exp Med. 2013;210(9):1855–69. doi: 10.1084/jem.20130091.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Brinkman CC, Peske JD, Engelhard VH. Peripheral tissue homing receptor control of naive, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues. Front Immunol. 2013;4:241. doi: 10.3389/fimmu.2013.00241.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Guo Y, Brown C, Ortiz C, Noelle RJ. Leukocyte homing, fate, and function are controlled by retinoic acid. Physiol Rev. 2015;95(1):125–48. doi: 10.1152/physrev.00032.2013.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008;8(9):685–98. doi: 10.1038/nri2378.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Edele F, Molenaar R, Gutle D, Dudda JC, Jakob T, Homey B, Mebius R, Hornef M, Martin SF. Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol. 2008;181(6):3745–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 2012;33(12):579–89. doi: 10.1016/j.it.2012.07.004.PubMedCrossRefGoogle Scholar
  113. 113.
    Marelli-Berg FM, Cannella L, Dazzi F, Mirenda V. The highway code of T cell trafficking. J Pathol. 2008;214(2):179–89. doi: 10.1002/path.2269.PubMedCrossRefGoogle Scholar
  114. 114.
    Heit B, Tavener S, Raharjo E, Kubes P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J Cell Biol. 2002;159(1):91–102. doi: 10.1083/jcb.200202114.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168–74. doi: 10.1158/0008-5472.CAN-14-2458.PubMedCrossRefGoogle Scholar
  116. 116.
    Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of Toll-like receptors in cancer. Oncogene. 2014;33(27):3485–95. doi: 10.1038/onc.2013.302.PubMedCrossRefGoogle Scholar
  117. 117.
    Garmy-Susini B, Varner JA. Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphat Res Biol. 2008;6(3–4):155–63. doi: 10.1089/lrb.2008.1011.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mumprecht V, Detmar M. Lymphangiogenesis and cancer metastasis. J Cell Mol Med. 2009;13(8A):1405–16. doi: 10.1111/j.1582-4934.2009.00834.x.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kilinc MO, Gu T, Harden JL, Virtuoso LP, Egilmez NK. Central role of tumor-associated CD8+ T effector/memory cells in restoring systemic antitumor immunity. J Immunol. 2009;182(7):4217–25. doi: 10.4049/jimmunol.0802793.PubMedCrossRefGoogle Scholar
  120. 120.
    Abastado JP. The next challenge in cancer immunotherapy: controlling T-cell traffic to the tumor. Cancer Res. 2012;72(9):2159–61. doi: 10.1158/0008-5472.CAN-11-3538.PubMedCrossRefGoogle Scholar
  121. 121.
    Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, Whittington M, Yang Y, Overwijk WW, Lizee G, Hwu P. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. 2010;16(22):5458–68. doi: 10.1158/1078-0432.CCR-10-0712.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Muller N, Michen S, Tietze S, Topfer K, Schulte A, Lamszus K, Schmitz M, Schackert G, Pastan I, Temme A. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting Glioblastoma. J Immunother. 2015;38(5):197–210. doi: 10.1097/CJI.0000000000000082.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911–23. doi: 10.1056/NEJMoa044396.PubMedCrossRefGoogle Scholar
  124. 124.
    Romme Christensen J, Ratzer R, Bornsen L, Lyksborg M, Garde E, Dyrby TB, Siebner HR, Sorensen PS, Sellebjerg F. Natalizumab in progressive MS: results of an open-label, phase 2A, proof-of-concept trial. Neurology. 2014;82(17):1499–507. doi: 10.1212/WNL.0000000000000361.PubMedCrossRefGoogle Scholar
  125. 125.
    Bryant RV, Sandborn WJ, Travis SP. Introducing vedolizumab to clinical practice: who, when, and how? J Crohns Colitis. 2015;9(4):356–66. doi: 10.1093/ecco-jcc/jjv033.PubMedCrossRefGoogle Scholar
  126. 126.
    Kivisakk P, Healy BC, Viglietta V, Quintana FJ, Hootstein MA, Weiner HL, Khoury SJ. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology. 2009;72(22):1922–30. doi: 10.1212/WNL.0b013e3181a8266f.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab—unforeseen consequences. N Engl J Med. 2005;353(4):414–6. doi: 10.1056/NEJMe058122.PubMedCrossRefGoogle Scholar
  128. 128.
    Kummer C, Ginsberg MH. New approaches to blockade of alpha4-integrins, proven therapeutic targets in chronic inflammation. Biochem Pharmacol. 2006;72(11):1460–8. doi: 10.1016/j.bcp.2006.06.014.PubMedCrossRefGoogle Scholar
  129. 129.
    Cantor JM, Ginsberg MH, Rose DM. Integrin-associated proteins as potential therapeutic targets. Immunol Rev. 2008;223:236–51. doi: 10.1111/j.1600-065X.2008.00640.x.PubMedCrossRefGoogle Scholar
  130. 130.
    Liu S, Thomas SM, Woodside DG, Rose DM, Kiosses WB, Pfaff M, Ginsberg MH. Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature. 1999;402(6762):676–81.PubMedCrossRefGoogle Scholar
  131. 131.
    Goldfinger LE, Han J, Kiosses WB, Howe AK, Ginsberg MH. Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration. J Cell Biol. 2003;162(4):731–41.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Nishiya N, Kiosses WB, Han J, Ginsberg MH. An alpha4 integrin-paxillin-Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nat Cell Biol. 2005;7(4):343–52.PubMedCrossRefGoogle Scholar
  133. 133.
    Liu S, Kiosses WB, Rose DM, Slepak M, Salgia R, Griffin JD, Turner CE, Schwartz MA, Ginsberg MH. A fragment of paxillin binds the alpha 4 integrin cytoplasmic domain (tail) and selectively inhibits alpha 4-mediated cell migration. J Biol Chem. 2002;277(23):20887–94. doi: 10.1074/jbc.M110928200.PubMedCrossRefGoogle Scholar
  134. 134.
    Han J, Rose DM, Woodside DG, Goldfinger LE, Ginsberg MH. Integrin alpha 4 beta 1-dependent T cell migration requires both phosphorylation and dephosphorylation of the alpha 4 cytoplasmic domain to regulate the reversible binding of paxillin. J Biol Chem. 2003;278(37):34845–53.PubMedCrossRefGoogle Scholar
  135. 135.
    Rose DM, Liu S, Woodside DG, Han J, Schlaepfer DD, Ginsberg MH. Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. J Immunol. 2003;170(12):5912–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Alon R, Feigelson SW, Manevich E, Rose DM, Schmitz J, Overby DR, Winter E, Grabovsky V, Shinder V, Matthews BD, Sokolovsky-Eisenberg M, Ingber DE, Benoit M, Ginsberg MH. Alpha4beta1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the alpha4-cytoplasmic domain. J Cell Biol. 2005;171(6):1073–84. doi: 10.1083/jcb.200503155.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Ambroise Y, Yaspan B, Ginsberg MH, Boger DL. Inhibitors of cell migration that inhibit intracellular paxillin/alpha4 binding: a well-documented use of positional scanning libraries. Chem Biol. 2002;9(11):1219–26.PubMedCrossRefGoogle Scholar
  138. 138.
    Kummer C, Petrich BG, Rose DM, Ginsberg MH. A small molecule that inhibits the interaction of paxillin and alpha 4 integrin inhibits accumulation of mononuclear leukocytes at a site of inflammation. J Biol Chem. 2010;285(13):9462–9. doi: 10.1074/jbc.M109.066993.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Feral CC, Rose DM, Han J, Fox N, Silverman GJ, Kaushansky K, Ginsberg MH. Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J Clin Invest. 2006;116(3):715–23.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Goldfinger LE, Tzima E, Stockton R, Kiosses WB, Kinbara K, Tkachenko E, Gutierrez E, Groisman A, Nguyen P, Chien S, Ginsberg MH. Localized alpha4 integrin phosphorylation directs shear stress-induced endothelial cell alignment. Circ Res. 2008;103(2):177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Ulyanova T, Priestley GV, Banerjee ER, Papayannopoulou T. Unique and redundant roles of alpha4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice. Exp Hematol. 2007;35(8):1256–65. doi: 10.1016/j.exphem.2007.04.015.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Overwijk WW, Restifo NP. B16 as a mouse model for human melanoma. Curr Protoc Immunol. 2001;Chapter 20:Unit 20 21.Google Scholar
  143. 143.
    Engelhardt B. Molecular mechanisms involved in T cell migration across the blood-brain barrier. J Neural Transm. 2006;113(4):477–85. doi: 10.1007/s00702-005-0409-y.PubMedCrossRefGoogle Scholar
  144. 144.
    Koboziev I, Karlsson F, Ostanin DV, Gray L, Davidson M, Zhang S, Grisham MB. Role of LFA-1 in the activation and trafficking of T cells: implications in the induction of chronic colitis. Inflamm Bowel Dis. 2012;18(12):2360–70. doi: 10.1002/ibd.22947.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Takeichi T, Mocevicius P, Deduchovas O, Salnikova O, Castro-Santa E, Buchler MW, Schmidt J, Ryschich E. alphaL beta2 integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer. Int J Cancer. 2012;130(9):2067–76. doi: 10.1002/ijc.26223.PubMedCrossRefGoogle Scholar
  146. 146.
    Henderson RB, Hobbs JA, Mathies M, Hogg N. Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood. 2003;102(1):328–35. doi: 10.1182/blood-2002-10-3228.PubMedCrossRefGoogle Scholar
  147. 147.
    Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol. 2004;4(6):432–44. doi: 10.1038/nri1375.PubMedCrossRefGoogle Scholar
  148. 148.
    Gjertsen BT, Mellgren G, Otten A, Maronde E, Genieser HG, Jastorff B, Vintermyr OK, McKnight GS, Doskeland SO. Novel (Rp)-cAMPS analogs as tools for inhibition of cAMP-kinase in cell culture. Basal cAMP-kinase activity modulates interleukin-1 beta action. J Biol Chem. 1995;270(35):20599–607.PubMedCrossRefGoogle Scholar
  149. 149.
    Grabbe S, Varga G, Beissert S, Steinert M, Pendl G, Seeliger S, Bloch W, Peters T, Schwarz T, Sunderkotter C, Scharffetter-Kochanek K. Beta2 integrins are required for skin homing of primed T cells but not for priming naive T cells. J Clin Invest. 2002;109(2):183–92. doi: 10.1172/JCI11703.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Reinhardt RL, Bullard DC, Weaver CT, Jenkins MK. Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation. J Exp Med. 2003;197(6):751–62. doi: 10.1084/jem.20021690.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Lee WY, Kubes P. Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs. J Hepatol. 2008;48(3):504–12. doi: 10.1016/j.jhep.2007.12.005.PubMedCrossRefGoogle Scholar
  152. 152.
    Lim CJ, Han J, Yousefi N, Ma Y, Amieux PS, McKnight GS, Taylor SS, Ginsberg MH. Alpha4 integrins are type I cAMP-dependent protein kinase-anchoring proteins. Nat Cell Biol. 2007;9(4):415–21. doi: 10.1038/ncb1561.Google Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of MedicineUniversity of California San DiegoLa JollaUSA

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