Cancer Immunology, Immunotherapy

, Volume 68, Issue 5, pp 835–847 | Cite as

Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism

  • Jingjing Zhu
  • Pierre-Florent Petit
  • Benoit J. Van den EyndeEmail author
Focussed Research Review


Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid-derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of “cold” tumors that fail to respond to immunotherapy. Interfering with the Fas–FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy.


Death receptors TIL apoptosis Cancer immunotherapy MDSC Fas ligand PIVAC 17 



Adoptive cell transfer


Activation-induced cell death


Protein kinase B


Autoimmune lymphoproliferative Syndrome


Antigen-presenting cells


Cancer-associated fibroblast


Cellular FLICE-inhibitory protein


Death domain


Epithelial-to-mesenchymal transition


Fas-associated death domain


Fas ligand


Genetically engineered mouse model


Hepatocyte growth factor




Melanoma-associated antigens


Monocyte-derived human macrophage


Matrix metalloproteinase


Non-small cell lung cancer




Programmed death ligand 2


Polymorphonuclear myeloid-derived suppressor cell


Tumor-associated macrophage


Anti-P1A T-cell receptor


TNF-like ligand 1A


Tumor microenvironment


TNF receptor-associated death domain


Regulatory T lymphocytes


Vascular endothelial growth factor



We are grateful to Ms. Auriane Sibille for her precious help in the preparation of this manuscript.

Author contributions

Jingjing Zhu and Benoit J. Van den Eynde conceived the manuscript. Pierre-Florent Petit designed the figures. All authors contributed to writing and revision of the manuscript.


Pierre-Florent Petit is supported by a fellowship from the Fonds National de la Recherche Scientifique (FNRS-Aspirant grant No. 1.A.818.18).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894. Google Scholar
  2. 2.
    Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF, KEYNOTE-024 Investigators (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026. Google Scholar
  3. 3.
    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. Google Scholar
  4. 4.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate Investigators (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. Google Scholar
  5. 5.
    Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015) Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 1:1. Google Scholar
  6. 6.
    Horton BL, Williams JB, Cabanov A, Spranger S, Gajewski TF (2018) Intratumoral CD8(+) T-cell apoptosis is a major component of T-cell dysfunction and impedes antitumor immunity. Cancer Immunol Res 6(1):14–24. Google Scholar
  7. 7.
    Zhu J, Powis de Tenbossche CG, Cane S, Colau D, van Baren N, Schmitt-Verhulst AM, Liljestrom P, Uyttenhove C, Van den Eynde B (2017) Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes. Nat Commun 8(1):1404Google Scholar
  8. 8.
    Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66(2):233–243Google Scholar
  9. 9.
    Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997) The receptor for the cytotoxic ligand TRAIL. Science 276(5309):111–113Google Scholar
  10. 10.
    Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277(5327):818–821Google Scholar
  11. 11.
    Loetscher H, Schlaeger EJ, Lahm HW, Pan YC, Lesslauer W, Brockhaus M (1990) Purification and partial amino acid sequence analysis of two distinct tumor necrosis factor receptors from HL60 cells. J Biol Chem 265(33):20131–20138Google Scholar
  12. 12.
    Chinnaiyan AM, O’Rourke K, Yu G-L, Lyons RH, Garg M, Duan DR, Xing L, Gentz R, Ni J, Dixit VM (1996) Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 274:990–992Google Scholar
  13. 13.
    Pan G, Ni J, Yu G, Wei YF, Dixit VM (1998) TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett 424(1–2):41–45Google Scholar
  14. 14.
    Suda T, Takahashi T, Golstein P, Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75:1169–1178Google Scholar
  15. 15.
    Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189–1192Google Scholar
  16. 16.
    Nagata S (1997) Apoptosis by death factor. Cell 88(3):355–365Google Scholar
  17. 17.
    Krammer PH (2000) CD95’s deadly mission in the immune system. Nature 407(6805):789–795. Google Scholar
  18. 18.
    Choi C, Park JY, Lee J, Lim JH, Shin EC, Ahn YS, Kim CH, Kim SJ, Kim JD, Choi IS, Choi IH (1999) Fas ligand and Fas are expressed constitutively in human astrocytes and the expression increases with IL-1, IL-6, TNF-alpha, or IFN-gamma. J Immunol 162(4):1889–1895Google Scholar
  19. 19.
    Tanaka M, Suda T, Takahashi T, Nagata S (1995) Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J 14:1129–1135Google Scholar
  20. 20.
    O’Reilly L, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A (2009) Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461(7264):659–663. Google Scholar
  21. 21.
    Nagata S, Suda T (1995) Fas and Fas ligand: lpr and gld mutations. Immunol Today 16(1):39–43Google Scholar
  22. 22.
    Ramsdell F, Seaman MS, Miller RE, Tough TW, Alderson MR, Lynch DH (1994) gld/gld mice are unable to express a functional ligand for Fas. Eur J Immunol 24(4):928–933. Google Scholar
  23. 23.
    Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH (1995) Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181(1):71–77Google Scholar
  24. 24.
    Hahne M, Rimoldi D, Schröter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Liénard D, Cerottini J-C, Tschopp J (1996) Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366Google Scholar
  25. 25.
    Restifo NP (2000) Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med 6:493–495Google Scholar
  26. 26.
    Seino K, Kayagaki N, Okumura K, Yagita H (1997) Antitumor effect of locally produced CD95 ligand. Nat Med 3(2):165–170Google Scholar
  27. 27.
    Arai H, Gordon D, Nabel EG, Nabel GJ (1997) Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 94(25):13862–13867Google Scholar
  28. 28.
    Ryan AE, Shanahan F, O’Connell J, Houston AM (2005) Addressing the “Fas counterattack” controversy: blocking Fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Cancer Res 65(21):9817–9823. Google Scholar
  29. 29.
    Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM (1999) Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet 64(4):1002–1014Google Scholar
  30. 30.
    Boselli D, Losana G, Bernabei P, Bosisio D, Drysdale P, Kiessling R, Gaston JS, Lammas D, Casanova JL, Kumararatne DS, Novelli F (2007) IFN-gamma regulates Fas ligand expression in human CD4+ T lymphocytes and controls their anti-mycobacterial cytotoxic functions. Eur J Immunol 37(8):2196–2204. Google Scholar
  31. 31.
    Le Gallo M, Poissonnier A, Blanco P, Legembre P (2017) CD95/Fas, non-apoptotic signaling pathways, and kinases. Front Immunol 8:1216. Google Scholar
  32. 32.
    Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, Sanchez-Perez L, Muranski P, Kern SJ, Logun C, Palmer DC, Ji Y, Reger RN, Leonard WJ, Danner RL, Rosenberg SA, Restifo NP (2009) Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA 106(41):17469–17474. Google Scholar
  33. 33.
    Klebanoff CA, Scott CD, Leonardi AJ, Yamamoto TN, Cruz AC, Ouyang C, Ramaswamy M, Roychoudhuri R, Ji Y, Eil RL, Sukumar M, Crompton JG, Palmer DC, Borman ZA, Clever D, Thomas SK, Patel S, Yu Z, Muranski P, Liu H, Wang E, Marincola FM, Gros A, Gattinoni L, Rosenberg SA, Siegel RM, Restifo NP (2016) Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Investig 126(1):318–334. Google Scholar
  34. 34.
    Kawasaki M, Kuwano K, Nakanishi Y, Hagimoto N, Takayama K, Pei XH, Maeyama T, Yoshimi M, Hara N (2000) Analysis of Fas and Fas ligand expression and function in lung cancer cell lines. Eur J Cancer 36(5):656–663Google Scholar
  35. 35.
    Ito Y, Monden M, Takeda T, Eguchi H, Umeshita K, Nagano H, Nakamori S, Dono K, Sakon M, Nakamura M, Tsujimoto M, Nakahara M, Nakao K, Yokosaki Y, Matsuura N (2000) The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma. Br J Cancer 82(6):1211–1217. Google Scholar
  36. 36.
    Bennett MW, O’Connell J, O’Sullivan GC, Brady C, Roche D, Collins JK, Shanahan F (1998) The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma. J Immunol 160(11):5669–5675Google Scholar
  37. 37.
    O’Connell J, O’Sullivan GC, Collins JK, Shanahan F (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184:1075–1082Google Scholar
  38. 38.
    Walker PR, Saas P, Dietrich PY (1998) Tumor expression of Fas ligand (CD95L) and the consequences. Curr Opin Immunol 10(5):564–572Google Scholar
  39. 39.
    Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7:297–303Google Scholar
  40. 40.
    Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ (2000) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113(Pt 19):3365–3374Google Scholar
  41. 41.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183(3):1161–1172Google Scholar
  42. 42.
    Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, Min WP (2005) Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 35(2):169–173. Google Scholar
  43. 43.
    Lin HC, Lai PY, Lin YP, Huang JY, Yang BC (2012) Fas ligand enhances malignant behavior of tumor cells through interaction with Met, hepatocyte growth factor receptor, in lipid rafts. J Biol Chem 287(24):20664–20673. Google Scholar
  44. 44.
    Merz C, Strecker A, Sykora J, Hill O, Fricke H, Angel P, Gieffers C, Peterziel H (2015) Neutralization of the CD95 ligand by APG101 inhibits invasion of glioma cells in vitro. Anticancer Drugs 26(7):716–727. Google Scholar
  45. 45.
    Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O, Thiemann M, Mueller W, Sykora J, Kuhn A, Schreglmann N, Letellier E, Zuliani C, Klussmann S, Teodorczyk M, Grone HJ, Ganten TM, Sultmann H, Tuttenberg J, von Deimling A, Regnier-Vigouroux A, Herold-Mende C, Martin-Villalba A (2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13(3):235–248. Google Scholar
  46. 46.
    Steller EJ, Borel Rinkes IH, Kranenburg O (2011) How CD95 stimulates invasion. Cell Cycle 10(22):3857–3862 Google Scholar
  47. 47.
    Wisniewski P, Ellert-Miklaszewska A, Kwiatkowska A, Kaminska B (2010) Non-apoptotic Fas signaling regulates invasiveness of glioma cells and modulates MMP-2 activity via NFkappaB-TIMP-2 pathway. Cell Signal 22(2):212–220. Google Scholar
  48. 48.
    Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W (2001) Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res 61(6):2744–2750Google Scholar
  49. 49.
    Wick W, Fricke H, Junge K, Kobyakov G, Martens T, Heese O, Wiestler B, Schliesser MG, von Deimling A, Pichler J, Vetlova E, Harting I, Debus J, Hartmann C, Kunz C, Platten M, Bendszus M, Combs SE (2014) A phase II, randomized, study of weekly APG101 + reirradiation versus reirradiation in progressive glioblastoma. Clin Cancer Res 20(24):6304–6313. Google Scholar
  50. 50.
    Teodorczyk M, Kleber S, Wollny D, Sefrin JP, Aykut B, Mateos A, Herhaus P, Sancho-Martinez I, Hill O, Gieffers C, Sykora J, Weichert W, Eisen C, Trumpp A, Sprick MR, Bergmann F, Welsch T, Martin-Villalba A (2015) CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma. Cell Death Differ 22(7):1192–1202. Google Scholar
  51. 51.
    Dudley AC (2012) Tumor endothelial cells. Cold Spring Harb Perspect Med 2(3):a006536. Google Scholar
  52. 52.
    Yu JS, Lee PK, Ehtesham M, Samoto K, Black KL, Wheeler CJ (2003) Intratumoral T cell subset ratios and Fas ligand expression on brain tumor endothelium. J Neurooncol 64(1–2):55–61Google Scholar
  53. 53.
    Bajou K, Peng H, Laug WE, Maillard C, Noel A, Foidart JM, Martial JA, DeClerck YA (2008) Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14(4):324–334. Google Scholar
  54. 54.
    Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20(6):607–615. Google Scholar
  55. 55.
    Tischner D, Woess C, Ottina E, Villunger A (2010) Bcl-2-regulated cell death signalling in the prevention of autoimmunity. Cell Death Dis 1:e48. Google Scholar
  56. 56.
    Tischner D, Gaggl I, Peschel I, Kaufmann M, Tuzlak S, Drach M, Thuille N, Villunger A, Jan Wiegers G (2012) Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice. J Autoimmun 38(1):59–69. Google Scholar
  57. 57.
    Veglia F, Perego M, Gabrilovich D (2018) Myeloid-derived suppressor cells coming of age. Nat Immunol 19(2):108–119. Google Scholar
  58. 58.
    Bronte V, Apolloni E, Cabrelle A, Ronca R, Serafini P, Zamboni P, Restifo NP, Zanovello P (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96(12):3838–3846Google Scholar
  59. 59.
    Kusmartsev SA, Li Y, Chen SH (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165(2):779–785Google Scholar
  60. 60.
    Condamine T, Ramachandran I, Youn JI, Gabrilovich DI (2015) Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med 66:97–110. Google Scholar
  61. 61.
    Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S (2011) Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood 117(20):5381–5390. Google Scholar
  62. 62.
    Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH (2014) Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy. J Immunol 192(12):5821–5829. Google Scholar
  63. 63.
    Peyvandi S, Buart S, Samah B, Vetizou M, Zhang Y, Durrieu L, Polrot M, Chouaib S, Benihoud K, Louache F, Karray S (2015) Fas ligand deficiency impairs tumor immunity by promoting an accumulation of monocytic myeloid-derived suppressor cells. Cancer Res 75(20):4292–4301. Google Scholar
  64. 64.
    Hailemichael Y, Dai Z, Jaffarzad N, Ye Y, Medina MA, Huang XF, Dorta-Estremera SM, Greeley NR, Nitti G, Peng W, Liu C, Lou Y, Wang Z, Ma W, Rabinovich B, Sowell RT, Schluns KS, Davis RE, Hwu P, Overwijk WW (2013) Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 19(4):465–472. Google Scholar
  65. 65.
    Huijbers IJ, Krimpenfort P, Chomez P, van der Valk MA, Song JY, Inderberg-Suso EM, Schmitt-Verhulst AM, Berns A, Van den Eynde BJ (2006) An inducible mouse model of melanoma expressing a defined tumor antigen. Cancer Res 66(6):3278–3286Google Scholar
  66. 66.
    Wehbe M, Soudja SM, Mas A, Chasson L, Guinamard R, de Tenbossche CP, Verdeil G, Van den Eynde B, Schmitt-Verhulst AM (2012) Epithelial–mesenchymal-transition-like and TGFbeta pathways associated with autochthonous inflammatory melanoma development in mice. PLoS One 7(11):e49419. Google Scholar
  67. 67.
    Soudja SM, Wehbe M, Mas A, Chasson L, de Tenbossche CP, Huijbers I, Van den Eynde B, Schmitt-Verhulst AM (2010) Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res 70:3515–3525. Google Scholar
  68. 68.
    Seino K, Iwabuchi K, Kayagaki N, Miyata R, Nagaoka I, Matsuzawa A, Fukao K, Yagita H, Okumura K (1998) Chemotactic activity of soluble Fas ligand against phagocytes. J Immunol 161(9):4484–4488Google Scholar
  69. 69.
    Ottonello L, Tortolina G, Amelotti M, Dallegri F (1999) Soluble Fas ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes. J Immunol 162(6):3601–3606Google Scholar
  70. 70.
    Hohlbaum AM, Moe S, Marshak-Rothstein A (2000) Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J Exp Med 191(7):1209–1220Google Scholar
  71. 71.
    Shudo K, Kinoshita K, Imamura R, Fan H, Hasumoto K, Tanaka M, Nagata S, Suda T (2001) The membrane-bound but not the soluble form of human Fas ligand is responsible for its inflammatory activity. Eur J Immunol 31(8):2504–2511.;2-C Google Scholar
  72. 72.
    Chen YL, Chen SH, Wang JY, Yang BC (2003) Fas ligand on tumor cells mediates inactivation of neutrophils. J Immunol 171(3):1183–1191Google Scholar
  73. 73.
    De Larco JE, Wuertz BR, Furcht LT (2004) The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 10(15):4895–4900. Google Scholar
  74. 74.
    Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P (2001) The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 97(2):339–345Google Scholar
  75. 75.
    Moses K, Brandau S (2016) Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol 28(2):187–196. Google Scholar
  76. 76.
    Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33(5):949–955. Google Scholar
  77. 77.
    Zhou J, Nefedova Y, Lei A, Gabrilovich D (2018) Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin Immunol 35:19–28. Google Scholar
  78. 78.
    Dockrell DH, Badley AD, Villacian JS, Heppelmann CJ, Algeciras A, Ziesmer S, Yagita H, Lynch DH, Roche PC, Leibson PJ, Paya CV (1998) The expression of Fas ligand by macrophages and its upregulation by human immunodeficiency virus infection. J Clin Investig 101(11):2394–2405. Google Scholar
  79. 79.
    Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA, Hartig H, Sundberg JP, Servick S, Kaufmann G, Fink PJ, Chervonsky AV (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26(5):629–641. Google Scholar
  80. 80.
    Ashany D, Savir A, Bhardwaj N, Elkon KB (1999) Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. J Immunol 163(10):5303–5311Google Scholar
  81. 81.
    Willems F, Amraoui Z, Vanderheyde N, Verhasselt V, Aksoy E, Scaffidi C, Peter ME, Krammer PH, Goldman M (2000) Expression of c-FLIP(L) and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide. Blood 95(11):3478–3482Google Scholar
  82. 82.
    Rescigno M, Piguet V, Valzasina B, Lens S, Zubler R, French L, Kindler V, Tschopp J, Ricciardi-Castagnoli P (2000) Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J Exp Med 192(11):1661–1668Google Scholar
  83. 83.
    Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD (2018) Cancer-associated fibroblasts induce antigen-specific deletion of CD8 (+) T Cells to protect tumour cells. Nat Commun 9(1):948. Google Scholar
  84. 84.
    Strauss L, Bergmann C, Whiteside TL (2009) Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol 182(3):1469–1480Google Scholar
  85. 85.
    Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, Krammer P, Linderkamp O, Suri-Payer E (2006) Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 108(10):3371–3378. Google Scholar
  86. 86.
    Plaza-Sirvent C, Schuster M, Neumann Y, Heise U, Pils MC, Schulze-Osthoff K, Schmitz I (2017) c-FLIP expression in Foxp3-expressing cells is essential for survival of regulatory T cells and prevention of autoimmunity. Cell Rep 18(1):12–22. Google Scholar
  87. 87.
    Hassin D, Garber OG, Meiraz A, Schiffenbauer YS, Berke G (2011) Cytotoxic T lymphocyte perforin and Fas ligand working in concert even when Fas ligand lytic action is still not detectable. Immunology 133(2):190–196. Google Scholar
  88. 88.
    Kameoka M, Suzuki S, Kimura T, Fujinaga K, Auwanit W, Luftig RB, Ikuta K (1997) Exposure of resting peripheral blood T cells to HIV-1 particles generates CD25+ killer cells in a small subset, leading to induction of apoptosis in bystander cells. Int Immunol 9(10):1453–1462Google Scholar
  89. 89.
    Hahn S, Gehri R, Erb P (1995) Mechanism and biological significance of CD4-mediated cytotoxicity. Immunol Rev 146:57–79Google Scholar
  90. 90.
    Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM (1997) An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277(5327):815–818Google Scholar
  91. 91.
    LeBlanc HN, Ashkenazi A (2003) Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10(1):66–75. Google Scholar
  92. 92.
    Wu GS, Burns TF, Zhan Y, Alnemri ES, El-Deiry WS (1999) Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res 59(12):2770–2775Google Scholar
  93. 93.
    Oikonomou E, Kothonidis K, Taoufik E, Probert E, Zografos G, Nasioulas G, Andera L, Pintzas A (2007) Newly established tumourigenic primary human colon cancer cell lines are sensitive to TRAIL-induced apoptosis in vitro and in vivo. Br J Cancer 97(1):73–84. Google Scholar
  94. 94.
    Walczak H (2013) Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harb Perspect Biol 5(5):a008698. Google Scholar
  95. 95.
    Liguori M, Buracchi C, Pasqualini F, Bergomas F, Pesce S, Sironi M, Grizzi F, Mantovani A, Belgiovine C, Allavena P (2016) Functional TRAIL receptors in monocytes and tumor-associated macrophages: a possible targeting pathway in the tumor microenvironment. Oncotarget 7(27):41662–41676. Google Scholar
  96. 96.
    Wendling U, Walczak H, Dorr J, Jaboci C, Weller M, Krammer PH, Zipp F (2000) Expression of TRAIL receptors in human autoreactive and foreign antigen-specific T cells. Cell Death Differ 7(7):637–644. Google Scholar
  97. 97.
    Jeremias I, Herr I, Boehler T, Debatin KM (1998) TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol 28(1):143–152.;2-3 Google Scholar
  98. 98.
    Lunemann JD, Waiczies S, Ehrlich S, Wendling U, Seeger B, Kamradt T, Zipp F (2002) Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells. J Immunol 168(10):4881–4888Google Scholar
  99. 99.
    Chyuan IT, Tsai HF, Wu CS, Sung CC, Hsu PN (2018) TRAIL-mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis. Front Immunol 9:15. Google Scholar
  100. 100.
    Dominguez GA, Condamine T, Mony S, Hashimoto A, Wang F, Liu Q, Forero A, Bendell J, Witt R, Hockstein N, Kumar P, Gabrilovich DI (2017) Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res 23(12):2942–2950. Google Scholar
  101. 101.
    Diao Z, Shi J, Zhu J, Yuan H, Ru Q, Liu S, Liu Y, Zheng D (2013) TRAIL suppresses tumor growth in mice by inducing tumor-infiltrating CD4(+)CD25 (+) Treg apoptosis. Cancer Immunol Immunother 62(4):653–663. Google Scholar
  102. 102.
    Vandenabeele P, Declercq W, Beyaert R, Fiers W (1995) Two tumour necrosis factor receptors: structure and function. Trends Cell Biol 5(10):392–399Google Scholar
  103. 103.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745–756. Google Scholar
  104. 104.
    Naude PJ, den Boer JA, Luiten PG, Eisel UL (2011) Tumor necrosis factor receptor cross-talk. FEBS J 278(6):888–898. Google Scholar
  105. 105.
    Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, Oshima M, Fujii C, Mukaida N (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Investig 118(2):560–570. Google Scholar
  106. 106.
    Zhaorigetu S, Yanaka N, Sasaki M, Watanabe H, Kato N (2003) Silk protein, sericin, suppresses DMBA-TPA-induced mouse skin tumorigenesis by reducing oxidative stress, inflammatory responses and endogenous tumor promoter TNF-alpha. Oncol Rep 10(3):537–543Google Scholar
  107. 107.
    Scott KA, Moore RJ, Arnott CH, East N, Thompson RG, Scallon BJ, Shealy DJ, Balkwill FR (2003) An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors. Mol Cancer Ther 2(5):445–451Google Scholar
  108. 108.
    Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, Wu H, Xu X, Erben U, Wu P, Syrbe U, Sieper J, Qin Z (2012) TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Investig 122(11):4094–4104. Google Scholar
  109. 109.
    Chen X, Oppenheim JJ (2011) Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS Lett 585(23):3611–3618. Google Scholar
  110. 110.
    Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR (1998) DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell 1(4):543–551Google Scholar
  111. 111.
    Pobezinskaya YL, Choksi S, Morgan MJ, Cao X, Liu ZG (2011) The adaptor protein TRADD is essential for TNF-like ligand 1A/death receptor 3 signaling. J Immunol 186(9):5212–5216. Google Scholar
  112. 112.
    Zeng L, Li T, Xu DC, Liu J, Mao G, Cui MZ, Fu X, Xu X (2012) Death receptor 6 induces apoptosis not through type I or type II pathways, but via a unique mitochondria-dependent pathway by interacting with Bax protein. J Biol Chem 287(34):29125–29133. Google Scholar
  113. 113.
    Vanamee ES, Faustman DL (2017) TNFR2: a novel target for cancer immunotherapy. Trends Mol Med 23(11):1037–1046. Google Scholar
  114. 114.
    Kunkele A, Johnson AJ, Rolczynski LS, Chang CA, Hoglund V, Kelly-Spratt KS, Jensen MC (2015) Functional tuning of CARs reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due to cell Fas–FasL-dependent AICD. Cancer Immunol Res 3(4):368–379. Google Scholar
  115. 115.
    Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y, Du L, Jiang J, Wu C, He X, Roberts AI, Li F, Rabson AB, Wang Y, Shi Y (2015) Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene 34(49):5960–5970. Google Scholar
  116. 116.
    Gastman BR, Johnson DE, Whiteside TL, Rabinowich H (2000) Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events. Blood 95(6):2015–2023Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ludwig Institute for Cancer ResearchBrusselsBelgium
  2. Duve InstituteUniversité catholique de LouvainBrusselsBelgium
  3. 3.Walloon Excellence in Life Sciences and BiotechnologyBrusselsBelgium

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