The observation that a subset of cancer patients show evidence for spontaneous CD8+ T cell priming against tumor-associated antigens has generated renewed interest in the innate immune pathways that might serve as a bridge to an adaptive immune response to tumors. Manipulation of this endogenous T cell response with therapeutic intent—for example, using blocking antibodies inhibiting PD-1/PD-L1 (programmed death-1/programmed death ligand 1) interactions—is showing impressive clinical results. As such, understanding the innate immune mechanisms that enable this T cell response has important clinical relevance. Defined innate immune interactions in the cancer context include recognition by innate cell populations (NK cells, NKT cells, and γδ T cells) and also by dendritic cells and macrophages in response to damage-associated molecular patterns (DAMPs). Recent evidence has indicated that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the stimulator of interferon gene (STING) pathway and driving type I IFN production. A deeper knowledge of the clinically relevant innate immune pathways involved in the recognition of tumors is leading toward new therapeutic strategies for cancer treatment.


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Literature Cited

  1. Boon T, Gajewski TF, Coulie PG. 1.  1995. From defined human tumor antigens to effective immunization?. Immunol. Today 16:334–36 [Google Scholar]
  2. Valmori D, Scheibenbogen C, Dutoit V, Nagorsen D, Asemissen AM. 2.  et al. 2002. Circulating tumor-reactive CD8+ T cells in melanoma patients contain a CD45RA+CCR7 effector subset exerting ex vivo tumor-specific cytolytic activity. Cancer Res. 62:1743–50 [Google Scholar]
  3. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M. 3.  et al. 2009. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69:3077–85 [Google Scholar]
  4. Speiser DE, Baumgaertner P, Barbey C, Rubio-Godoy V, Moulin A. 4.  et al. 2006. A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination. J. Immunol. 177:1338–48 [Google Scholar]
  5. Anichini A, Molla A, Mortarini R, Tragni G, Bersani I. 5.  et al. 1999. An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions. J. Exp. Med. 190:651–67 [Google Scholar]
  6. Wang X, Yu J, Sreekumar A, Varambally S, Shen R. 6.  et al. 2005. Autoantibody signatures in prostate cancer. N. Engl. J. Med. 353:1224–35 [Google Scholar]
  7. Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C. 7.  et al. 2013. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19:747–52 [Google Scholar]
  8. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M. 8.  et al. 2013. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31:e439–42 [Google Scholar]
  9. Kvistborg P, van Buuren MM, Schumacher TN. 9.  2013. Human cancer regression antigens. Curr. Opin. Immunol. 25:284–90 [Google Scholar]
  10. Markiewicz MA, Gajewski TF. 10.  1999. The immune system as anti-tumor sentinel: molecular requirements for an anti-tumor immune response. Crit. Rev. Oncog. 10:247–60 [Google Scholar]
  11. Gajewski TF, Louahed J, Brichard VG. 11.  2010. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16:399–403 [Google Scholar]
  12. Gajewski TF, Schreiber H, Fu YX. 12.  2013. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14:1014–22 [Google Scholar]
  13. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y. 13.  et al. 2013. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5:200ra116 [Google Scholar]
  14. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. 14.  2014. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J. Immunother. Cancer 2:3 [Google Scholar]
  15. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H. 15.  et al. 2012. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61:1019–31 [Google Scholar]
  16. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S. 16.  et al. 2011. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9:204 [Google Scholar]
  17. Joseph RW, Eckel-Passow JE, Sharma R, Liu P, Parker A. 17.  et al. 2012. Characterizing the clinical benefit of ipilimumab in patients who progressed on high-dose IL-2. J. Immunother. 35:711–15 [Google Scholar]
  18. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC. 18.  et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–54 [Google Scholar]
  19. Ascierto ML, Idowu MO, Zhao Y, Khalak H, Payne KK. 19.  et al. 2013. Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients. J. Transl. Med. 11:145 [Google Scholar]
  20. Tachibana T, Onodera H, Tsuruyama T, Mori A, Nagayama S. 20.  et al. 2005. Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin. Cancer Res. 11:7322–27 [Google Scholar]
  21. Ma C, Zhang Q, Ye J, Wang F, Zhang Y. 21.  et al. 2012. Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. J. Immunol. 189:5029–36 [Google Scholar]
  22. Diefenbach A, Colonna M, Koyasu S. 22.  2014. Development, differentiation, and diversity of innate lymphoid cells. Immunity 41:354–65 [Google Scholar]
  23. Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA. 23.  et al. 1997. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79:2320–28 [Google Scholar]
  24. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X. 24.  et al. 2000. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88:577–83 [Google Scholar]
  25. Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ. 25.  et al. 2002. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 35:23–28 [Google Scholar]
  26. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F. 26.  et al. 2008. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571–80 [Google Scholar]
  27. Mishra R, Chen AT, Welsh RM, Szomolanyi-Tsuda E. 27.  2010. NK cells and γδ T cells mediate resistance to polyomavirus-induced tumors. PLOS Pathog. 6:e1000924 [Google Scholar]
  28. Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. 28.  2005. NKG2D function protects the host from tumor initiation. J. Exp. Med. 202:583–88 [Google Scholar]
  29. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA. 29.  et al. 2000. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191:661–68 [Google Scholar]
  30. Smyth MJ, Crowe NY, Godfrey DI. 30.  2001. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13:459–63 [Google Scholar]
  31. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M. 31.  et al. 2003. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198:557–67 [Google Scholar]
  32. Masson D, Jarry A, Baury B, Blanchardie P, Laboisse C. 32.  et al. 2001. Overexpression of the CD155 gene in human colorectal carcinoma. Gut 49:236–40 [Google Scholar]
  33. Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F. 33.  et al. 2009. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J. Clin. Investig. 119:1251–63 [Google Scholar]
  34. Iguchi-Manaka A, Kai H, Yamashita Y, Shibata K, Tahara-Hanaoka S. 34.  et al. 2008. Accelerated tumor growth in mice deficient in DNAM-1 receptor. J. Exp. Med. 205:2959–64 [Google Scholar]
  35. Liu XV, Ho SS, Tan JJ, Kamran N, Gasser S. 35.  2012. Ras activation induces expression of Raet1 family NK receptor ligands. J. Immunol. 189:1826–34 [Google Scholar]
  36. Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH. 36.  2012. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J. Exp. Med. 209:2409–22 [Google Scholar]
  37. Gasser S, Orsulic S, Brown EJ, Raulet DH. 37.  2005. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186–90 [Google Scholar]
  38. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR. 38.  et al. 2009. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113:3503–11 [Google Scholar]
  39. Ardolino M, Zingoni A, Cerboni C, Cecere F, Soriani A. 39.  et al. 2011. DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction. Blood 117:4778–86 [Google Scholar]
  40. Lord CJ, Ashworth A. 40.  2012. The DNA damage response and cancer therapy. Nature 481:287–94 [Google Scholar]
  41. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F. 41.  et al. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–70 [Google Scholar]
  42. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A. 42.  et al. 2005. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–13 [Google Scholar]
  43. Waldhauer I, Steinle A. 43.  2008. NK cells and cancer immunosurveillance. Oncogene 27:5932–43 [Google Scholar]
  44. Liu RB, Engels B, Arina A, Schreiber K, Hyjek E. 44.  et al. 2012. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res. 72:1964–74 [Google Scholar]
  45. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. 45.  2013. NK cell-based immunotherapy for malignant diseases. Cell Mol. Immunol. 10:230–52 [Google Scholar]
  46. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M. 46.  et al. 2004. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5:1260–65 [Google Scholar]
  47. Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H. 47.  et al. 2003. Natural killer cells activated by MHC class ILow targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19:561–69 [Google Scholar]
  48. Kelly JM, Darcy PK, Markby JL, Godfrey DI, Takeda K. 48.  et al. 2002. Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat. Immunol. 3:83–90 [Google Scholar]
  49. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. 49.  2013. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31:413–41 [Google Scholar]
  50. Groh V, Wu J, Yee C, Spies T. 50.  2002. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419:734–38 [Google Scholar]
  51. Jinushi M, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R. 51.  et al. 2005. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J. Hepatol. 43:1013–20 [Google Scholar]
  52. Nuckel H, Switala M, Sellmann L, Horn PA, Durig J. 52.  et al. 2010. The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. Leukemia 24:1152–59 [Google Scholar]
  53. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M. 53.  et al. 2014. Recognition of tumors by the innate immune system and natural killer cells. Adv. Immunol. 122:91–128 [Google Scholar]
  54. Coudert JD, Scarpellino L, Gros F, Vivier E, Held W. 54.  2008. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 111:3571–78 [Google Scholar]
  55. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ. 55.  et al. 2002. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661–67 [Google Scholar]
  56. Crome SQ, Lang PA, Lang KS, Ohashi PS. 56.  2013. Natural killer cells regulate diverse T cell responses. Trends Immunol. 34:342–49 [Google Scholar]
  57. Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S. 57.  et al. 2011. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat. Med. 17:700–7 [Google Scholar]
  58. Zhang T, Lemoi BA, Sentman CL. 58.  2005. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106:1544–51 [Google Scholar]
  59. Barber A, Rynda A, Sentman CL. 59.  2009. Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J. Immunol. 183:6939–47 [Google Scholar]
  60. Jinushi M, Hodi FS, Dranoff G. 60.  2006. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. PNAS 103:9190–95 [Google Scholar]
  61. Lam AR, Le Bert N, Ho SS, Shen YJ, Tang ML. 61.  et al. 2014. RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res. 74:2193–203 [Google Scholar]
  62. Crowe NY, Smyth MJ, Godfrey DI. 62.  2002. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med. 196:119–27 [Google Scholar]
  63. Swann JB, Uldrich AP, van Dommelen S, Sharkey J, Murray WK. 63.  et al. 2009. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113:6382–85 [Google Scholar]
  64. Lantz O, Bendelac A. 64.  1994. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I–specific CD4+ and CD48 T cells in mice and humans. J. Exp. Med. 180:1097–106 [Google Scholar]
  65. Bendelac A. 65.  1995. CD1 recognition by mouse NK1+ T lymphocytes. Science 268:863–65 [Google Scholar]
  66. Kawano T. 66.  1997. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626–29 [Google Scholar]
  67. Zhou D. 67.  2004. Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–89 [Google Scholar]
  68. Mannik LA, Chin-Yee I, Sharif S, Van Kaer L, Delovitch TL, Haeryfar SM. 68.  2011. Engagement of glycosylphosphatidylinositol-anchored proteins results in enhanced mouse and human invariant natural killer T cell responses. Immunology 132:361–75 [Google Scholar]
  69. Joyce S, Woods AS, Yewdell JW, Bennink JR, De Silva AD. 69.  et al. 1998. Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science 279:1541–44 [Google Scholar]
  70. Wu DY, Segal NH, Sidobre S, Kronenberg M, Chapman PB. 70.  2003. Cross-presentation of disialoganglioside GD3 to natural killer T cells. J. Exp. Med. 198:173–81 [Google Scholar]
  71. Ambrosino E, Terabe M, Halder RC, Peng J, Takaku S. 71.  et al. 2007. Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis. J. Immunol. 179:5126–36 [Google Scholar]
  72. Berzofsky JA, Terabe M. 72.  2008. A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity. Cancer Immunol. Immunother. 57:1679–83 [Google Scholar]
  73. Matsuda JL, Mallevaey T, Scott-Browne J, Gapin L. 73.  2008. CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system. Curr. Opin. Immunol. 20:358–68 [Google Scholar]
  74. Raghuraman G, Geng Y, Wang CR. 74.  2006. IFN-beta-mediated up-regulation of CD1d in bacteria-infected APCs. J. Immunol. 177:7841–48 [Google Scholar]
  75. Van Kaer L, Parekh VV, Wu L. 75.  2011. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res. 343:43–55 [Google Scholar]
  76. Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM. 76.  2003. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198:267–79 [Google Scholar]
  77. Parekh VV, Wilson MT, Olivares-Villagomez D, Singh AK, Wu L. 77.  et al. 2005. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115:2572–83 [Google Scholar]
  78. Terabe M, Berzofsky JA. 78.  2008. The role of NKT cells in tumor immunity. Adv. Cancer Res. 101:277–348 [Google Scholar]
  79. Moreno M, Molling JW, von Mensdorff-Pouilly S, Verheijen RH, Hooijberg E. 79.  et al. 2008. IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. J. Immunol. 181:2446–54 [Google Scholar]
  80. Shimizu K, Mizuno T, Shinga J, Asakura M, Kakimi K. 80.  et al. 2013. Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells. Cancer Res. 73:62–73 [Google Scholar]
  81. Richter J, Neparidze N, Zhang L, Nair S, Monesmith T. 81.  et al. 2013. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423–30 [Google Scholar]
  82. Gehrmann U, Hiltbrunner S, Georgoudaki AM, Karlsson MC, Naslund TI, Gabrielsson S. 82.  2013. Synergistic induction of adaptive antitumor immunity by codelivery of antigen with alpha-galactosylceramide on exosomes. Cancer Res. 73:3865–76 [Google Scholar]
  83. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C. 83.  et al. 2000. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat. Immunol. 1:515–20 [Google Scholar]
  84. Corvaisier M, Moreau-Aubry A, Diez E, Bennouna J, Mosnier JF. 84.  et al. 2005. Vγ9Vδ2 T cell response to colon carcinoma cells. J. Immunol. 175:5481–88 [Google Scholar]
  85. Liu Z, Guo BL, Gehrs BC, Nan L, Lopez RD. 85.  2005. Ex vivo expanded human Vλ9Vδ2 +λδ-T cells mediate innate antitumor activity against human prostate cancer cells in vitro. J. Urol. 173:1552–56 [Google Scholar]
  86. Viey E, Fromont G, Escudier B, Morel Y, Da Rocha S. 86.  et al. 2005. Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma. J. Immunol. 174:1338–47 [Google Scholar]
  87. Burjanadze M, Condomines M, Reme T, Quittet P, Latry P. 87.  et al. 2007. In vitro expansion of gamma delta T cells with anti-myeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma. Br. J. Haematol. 139:206–16 [Google Scholar]
  88. Saitoh A, Narita M, Watanabe N, Tochiki N, Satoh N. 88.  et al. 2008. Anti-tumor cytotoxicity of γδ T cells expanded from peripheral blood cells of patients with myeloma and lymphoma. Med. Oncol. 25:137–47 [Google Scholar]
  89. Kabelitz D, Wesch D, Pitters E, Zoller M. 89.  2004. Characterization of tumor reactivity of human Vγ9Vδ2 γδ T cells in vitro and in SCID mice in vivo. J. Immunol. 173:6767–76 [Google Scholar]
  90. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E. 90.  et al. 2001. Regulation of cutaneous malignancy by γδ T cells. Science 294:605–9 [Google Scholar]
  91. Mattarollo SR, Kenna T, Nieda M, Nicol AJ. 91.  2007. Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity. Cancer Immunol. Immunother. 56:1285–97 [Google Scholar]
  92. Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G. 92.  2003. Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 197:163–68 [Google Scholar]
  93. Chien YH, Konigshofer Y. 93.  2007. Antigen recognition by γδ T cells. Immunol. Rev. 215:46–58 [Google Scholar]
  94. Scotet E. 94.  2005. Tumor recognition following Vγ9Vδ2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71–80 [Google Scholar]
  95. Luoma AM, Castro CD, Mayassi T, Bembinster LA, Bai L. 95.  et al. 2013. Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity 39:1032–42 [Google Scholar]
  96. Thedrez A. 96.  2007. Self/non-self discrimination by human γδ T cells: simple solutions for a complex issue?. Immunol. Rev. 215:123–35 [Google Scholar]
  97. Raulet DH, Guerra N. 97.  2009. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat. Rev. Immunol. 9:568–78 [Google Scholar]
  98. Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K. 98.  et al. 2008. Zoledronate facilitates large-scale ex vivo expansion of functional γδ T cells from cancer patients for use in adoptive immunotherapy. Cytotherapy 10:842–56 [Google Scholar]
  99. Tokuyama H, Hagi T, Mattarollo SR, Morley J, Wang Q. 99.  et al. 2008. Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—rituximab and trastuzumab. Int. J. Cancer 122:2526–34 [Google Scholar]
  100. Do JS, Min B. 100.  2009. IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and γδ T cells in vivo. Blood 113:6361–71 [Google Scholar]
  101. Marcu-Malina V, Heijhuurs S, van Buuren M, Hartkamp L, Strand S. 101.  et al. 2011. Redirecting αβT cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor. Blood 118:50–59 [Google Scholar]
  102. Martinet L, Fleury-Cappellesso S, Gadelorge M, Dietrich G, Bourin P. 102.  et al. 2009. A regulatory cross-talk between Vγ9Vδ2 T lymphocytes and mesenchymal stem cells. Eur. J. Immunol. 39:752–62 [Google Scholar]
  103. Kunzmann V, Kimmel B, Herrmann T, Einsele H, Wilhelm M. 103.  2009. Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells. Immunology 126:256–67 [Google Scholar]
  104. Martinet L, Poupot R, Fournie JJ. 104.  2009. Pitfalls on the roadmap to γδ T cell-based cancer immunotherapies. Immunol. Lett. 124:1–8 [Google Scholar]
  105. Peng G. 105.  2007. Tumor-infiltrating γδ T cells suppress T and dendritic cell function via mechanisms controlled by a unique Toll-like receptor signalling pathway. Immunity 27:334–48 [Google Scholar]
  106. Carlo E, Bocca P, Emionite L, Cilli M, Cipollone G. 106.  Di et al. 2013. Mechanisms of the antitumor activity of human Vγ9Vδ2 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma. Mol. Ther. 21:1034–43 [Google Scholar]
  107. Kobayashi H, Tanaka Y, Nakazawa H, Yagi J, Minato N, Tanabe K. 107.  2011. A new indicator of favorable prognosis in locally advanced renal cell carcinomas: γδ T-cells in peripheral blood. Anticancer Res. 31:1027–31 [Google Scholar]
  108. Fisher JP, Heuijerjans J, Yan M, Gustafsson K, Anderson J. 108.  2014. γδ T cells for cancer immunotherapy: a systematic review of clinical trials. Oncoimmunology 3:e27572 [Google Scholar]
  109. Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G. 109.  2007. Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J. Immunol. 178:1534–41 [Google Scholar]
  110. den Haan JM, Lehar SM, Bevan MJ. 110.  2000. CD8+ but not CD8 dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192:1685–96 [Google Scholar]
  111. Villadangos JA, Schnorrer P. 111.  2007. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat. Rev. Immunol. 7:543–55 [Google Scholar]
  112. Liu C, Lou Y, Lizee G, Qin H, Liu S. 112.  et al. 2008. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J. Clin. Investig. 118:1165–75 [Google Scholar]
  113. Wei S, Kryczek I, Zou L, Daniel B, Cheng P. 113.  et al. 2005. Plasmacytoid dendritic cells induce CD8+regulatory T cells in human ovarian carcinoma. Cancer Res. 65:5020–26 [Google Scholar]
  114. Labidi-Galy SI, Treilleux I, Goddard-Leon S, Combes JD, Blay JY. 114.  et al. 2012. Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis. Oncoimmunology 1:380–82 [Google Scholar]
  115. Demoulin S, Herfs M, Delvenne P, Hubert P. 115.  2013. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J. Leukoc. Biol. 93:343–52 [Google Scholar]
  116. Sisirak V, Faget J, Gobert M, Goutagny N, Vey N. 116.  et al. 2012. Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res. 72:5188–97 [Google Scholar]
  117. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. 117.  2008. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol. 181:5396–404 [Google Scholar]
  118. Watkins SK. 118.  2011. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J. Clin. Investig. 121:1361–72 [Google Scholar]
  119. Sancho D, Mourao-Sa D, Joffre OP, Schulz O, Rogers NC. 119.  et al. 2008. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Investig. 118:2098–110 [Google Scholar]
  120. Ahrens S. 120.  2012. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36:635–45 [Google Scholar]
  121. Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D. 121.  et al. 2009. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458:899–903 [Google Scholar]
  122. Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L. 122.  et al. 2010. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells. J. Exp. Med. 207:1261–71 [Google Scholar]
  123. Crozat K, Guiton R, Contreras V, Feuillet V, Dutertre CA. 123.  et al. 2010. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells. J. Exp. Med. 207:1283–92 [Google Scholar]
  124. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H. 124.  et al. 2008. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322:1097–100 [Google Scholar]
  125. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM. 125.  et al. 2011. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208:2005–16 [Google Scholar]
  126. Bingle L, Brown NJ, Lewis CE. 126.  2002. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196:254–65 [Google Scholar]
  127. Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY. 127.  et al. 2005. Tumor-associated macrophages: the double-edged sword in cancer progression. J. Clin. Oncol. 23:953–64 [Google Scholar]
  128. Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA. 128.  2008. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr. Relat. Cancer 15:1069–74 [Google Scholar]
  129. Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B. 129.  et al. 2010. An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70:1323–33 [Google Scholar]
  130. Medrek C, Ponten F, Jirstrom K, Leandersson K. 130.  2012. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer 12:306 [Google Scholar]
  131. Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI. 131.  et al. 2012. Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood 120:3280–87 [Google Scholar]
  132. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH. 132.  et al. 2012. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLOS One 7:e50946 [Google Scholar]
  133. Chitu V, Stanley ER. 133.  2006. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18:39–48 [Google Scholar]
  134. Mantovani A, Savino B, Locati M, Zammataro L, Allavena P, Bonecchi R. 134.  2010. The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev. 21:27–39 [Google Scholar]
  135. Hagemann T, Wilson J, Burke F, Kulbe H, Li NF. 135.  et al. 2006. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol. 176:5023–32 [Google Scholar]
  136. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F. 136.  et al. 2004. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64:7022–29 [Google Scholar]
  137. Lin EY, Nguyen AV, Russell RG, Pollard JW. 137.  2001. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193:727–40 [Google Scholar]
  138. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J. 138.  et al. 2011. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–325 [Google Scholar]
  139. Mantovani A, Allavena P, Sica A, Balkwill F. 139.  2008. Cancer-related inflammation. Nature 454:436–44 [Google Scholar]
  140. Kessenbrock K, Plaks V, Werb Z. 140.  2010. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67 [Google Scholar]
  141. Lin EY. 141.  2006. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66:11238–46 [Google Scholar]
  142. Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S. 142.  et al. 2010. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J. Immunol. 185:642–52 [Google Scholar]
  143. Kuang DM. 143.  2009. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206:1327–37 [Google Scholar]
  144. Torroella-Kouri M. 144.  2009. Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res. 69:4800–9 [Google Scholar]
  145. Curiel TJ. 145.  2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10:942–49 [Google Scholar]
  146. DeNardo DG. 146.  2009. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102 [Google Scholar]
  147. Duluc D, Corvaisier M, Blanchard S, Catala L, Descamps P. 147.  et al. 2009. Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int. J. Cancer 125:367–73 [Google Scholar]
  148. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. 148.  2005. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65:3437–46 [Google Scholar]
  149. Wang YC, He F, Feng F, Liu XW, Dong GY. 149.  et al. 2010. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70:4840–49 [Google Scholar]
  150. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M. 150.  et al. 2012. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. PNAS 109:17561–66 [Google Scholar]
  151. Gonzalez-Navajas JM, Lee J, David M, Raz E. 151.  2012. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12:125–35 [Google Scholar]
  152. Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF. 152.  2013. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34:67–73 [Google Scholar]
  153. Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP. 153.  et al. 2011. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208:1989–2003 [Google Scholar]
  154. Devilder MC, Allain S, Dousset C, Bonneville M, Scotet E. 154.  2009. Early triggering of exclusive IFN-γ responses of human Vγ9Vδ2 T cells by TLR-activated myeloid and plasmacytoid dendritic cells. J. Immunol. 183:3625–33 [Google Scholar]
  155. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E. 155.  et al. 2008. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299–311 [Google Scholar]
  156. Yang X, Zhang X, Fu ML, Weichselbaum RR, Gajewski TF. 156.  et al. 2014. Targeting the tumor microenvironment with interferon-beta bridges innate and adaptive immune responses. Cancer Cell 25:37–48 [Google Scholar]
  157. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN. 157.  et al. 2011. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 71:2488–96 [Google Scholar]
  158. Swann JB, Hayakawa Y, Zerafa N, Sheehan KC, Scott B. 158.  et al. 2007. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J. Immunol. 178:7540–49 [Google Scholar]
  159. U'Ren L, Guth A, Kamstock D, Dow S. 159.  2010. Type I interferons inhibit the generation of tumor-associated macrophages. Cancer Immunol. Immunother. 59:587–98 [Google Scholar]
  160. Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ. 160.  et al. 2014. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–42 [Google Scholar]
  161. Barbalat R, Ewald SE, Mouchess ML, Barton GM. 161.  2011. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29:185–214 [Google Scholar]
  162. Kono H, Rock KL. 162.  2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8:279–89 [Google Scholar]
  163. Rathinam VA, Fitzgerald KA. 163.  2011. Cytosolic surveillance and antiviral immunity. Curr. Opin. Virol. 1:455–62 [Google Scholar]
  164. Crow MK. 164.  2007. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316:359–86 [Google Scholar]
  165. Reich CF 3rd, Pisetsky DS. 165.  2009. The content of DNA and RNA in microparticles released by Jurkat and HL-60 cells undergoing in vitro apoptosis. Exp. Cell Res. 315:760–68 [Google Scholar]
  166. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. 166.  2005. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6:49–56 [Google Scholar]
  167. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. 167.  2000. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25:177–81 [Google Scholar]
  168. Green DR, Ferguson T, Zitvogel L, Kroemer G. 168.  2009. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9:353–63 [Google Scholar]
  169. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. 169.  2013. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31:51–72 [Google Scholar]
  170. Obeid M. 170.  2007. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13:54–61 [Google Scholar]
  171. Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. 171.  2011. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71:4809–20 [Google Scholar]
  172. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. 172.  2012. The emergence of phox-ER stress induced immunogenic apoptosis. OncoImmunology 1:787–89 [Google Scholar]
  173. Dudek AM, Garg AD, Krysko DV, De Ruysscher D, Agostinis P. 173.  2013. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev. 24:319–33 [Google Scholar]
  174. Garg AD. 174.  2012. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31:1062–79 [Google Scholar]
  175. Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F. 175.  et al. 2008. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 15:3–12 [Google Scholar]
  176. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. 176.  2012. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12:860–75 [Google Scholar]
  177. Garg AD. 177.  2010. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim. Biophys. Acta 1805:53–71 [Google Scholar]
  178. Muller S, Ronfani L, Bianchi ME. 178.  2004. Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J. Intern. Med. 255:332–43 [Google Scholar]
  179. Apetoh L. 179.  2007. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13:1050–59 [Google Scholar]
  180. Jube S. 180.  2012. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 72:3290–301 [Google Scholar]
  181. Yang GL. 181.  2012. Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer. J. Surg. Oncol. 106:57–61 [Google Scholar]
  182. Chiba S. 182.  2012. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13:832–42 [Google Scholar]
  183. Venereau E. 183.  2012. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209:1519–28 [Google Scholar]
  184. Yang H. 184.  2012. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol. Med. 18:250–59 [Google Scholar]
  185. MacLennan DH, Yip CC, Iles GH, Seeman P. 185.  1972. Isolation of sarcoplasmic reticulum proteins. Cold Spring Harb. Symp. Quant. Biol. 37:469–77 [Google Scholar]
  186. Obeid M, Tesniere A, Panaretakis T, Tufi R, Joza N. 186.  et al. 2007. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220:22–34 [Google Scholar]
  187. Miyamoto S. 187.  2012. Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma. Cancer Res. 72:2609–21 [Google Scholar]
  188. Gardai SJ. 188.  2005. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–34 [Google Scholar]
  189. Pawaria S, Binder RJ. 189.  2011. CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat. Commun. 2:521 [Google Scholar]
  190. Panaretakis T. 190.  2009. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28:578–90 [Google Scholar]
  191. Wemeau M, Kepp O, Tesniere A, Panaretakis T, Flament C. 191.  et al. 2010. Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia. Cell Death Dis. 1:e104 [Google Scholar]
  192. Peng RQ, Chen YB, Ding Y, Zhang R, Zhang X. 192.  et al. 2010. Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer. World J. Gastroenterol. 16:2428–34 [Google Scholar]
  193. Martins I. 193.  2009. Chemotherapy induces ATP release from tumor cells. Cell Cycle 8:3723–28 [Google Scholar]
  194. Michaud M. 194.  2011. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334:1573–77 [Google Scholar]
  195. Martins I. 195.  2012. Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy 8:413–15 [Google Scholar]
  196. Elliott MR. 196.  2009. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282–86 [Google Scholar]
  197. Ghiringhelli F. 197.  2009. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15:1170–78 [Google Scholar]
  198. Mortensen SP, Thaning P, Nyberg M, Saltin B, Hellsten Y. 198.  2011. Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: insight from ATP determination with the intravascular microdialysis technique. J. Physiol. 589:1847–57 [Google Scholar]
  199. Robson SC, Sevigny J, Zimmermann H. 199.  2006. The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal. 2:409–30 [Google Scholar]
  200. Beavis PA, Stagg J, Darcy PK, Smyth MJ. 200.  2012. CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 33:231–37 [Google Scholar]
  201. Stagg J. 201.  2012. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72:2190–96 [Google Scholar]
  202. Ohta A. 202.  2006. A2A adenosine receptor protects tumors from antitumor T cells. PNAS 103:13132–37 [Google Scholar]
  203. Markiewski MM, Lambris JD. 203.  2009. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 30:286–92 [Google Scholar]
  204. Walport MJ. 204.  2001. Complement. N. Engl. J. Med. 344:1058–66 [Google Scholar]
  205. Ricklin D, Hajishengallis G, Yang K, Lambris JD. 205.  2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11:785–97 [Google Scholar]
  206. Gasque P, Thomas A, Fontaine M, Morgan BP. 206.  1996. Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. J. Neuroimmunol. 66:29–40 [Google Scholar]
  207. Lucas SD, Karlsson-Parra A, Nilsson B, Grimelius L, Akerstrom G. 207.  et al. 1996. Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Hum. Pathol. 27:1329–35 [Google Scholar]
  208. Niculescu F, Rus HG, Retegan M, Vlaicu R. 208.  1992. Persistent complement activation on tumor cells in breast cancer. Am. J. Pathol. 140:1039–43 [Google Scholar]
  209. Ajona D, Pajares MJ, Corrales L, Perez-Gracia JL, Agorreta J. 209.  et al. 2013. Investigation of complement activation product C4d as a diagnostic and prognostic biomarker for lung cancer. J. Natl. Cancer Inst. 105:1385–93 [Google Scholar]
  210. Bjorge L, Hakulinen J, Vintermyr OK, Jarva H, Jensen TS. 210.  et al. 2005. Ascitic complement system in ovarian cancer. Br. J. Cancer 92:895–905 [Google Scholar]
  211. Corrales L, Ajona D, Rafail S, Lasarte JJ, Riezu-Boj JI. 211.  et al. 2012. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J. Immunol. 189:4674–83 [Google Scholar]
  212. Ytting H, Christensen IJ, Thiel S, Jensenius JC, Nielsen HJ. 212.  2005. Serum mannan-binding lectin-associated serine protease 2 levels in colorectal cancer: relation to recurrence and mortality. Clin. Cancer Res. 11:1441–46 [Google Scholar]
  213. Jurianz K, Ziegler S, Garcia-Schuler H, Kraus S, Bohana-Kashtan O. 213.  et al. 1999. Complement resistance of tumor cells: basal and induced mechanisms. Mol. Immunol. 36:929–39 [Google Scholar]
  214. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. 214.  2003. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol. Immunol. 40:109–23 [Google Scholar]
  215. Gancz D, Fishelson Z. 215.  2009. Cancer resistance to complement-dependent cytotoxicity (CDC): problem-oriented research and development. Mol. Immunol. 46:2794–800 [Google Scholar]
  216. Pio R, Garcia J, Corrales L, Ajona D, Fleischhacker M. 216.  et al. 2010. Complement factor H is elevated in bronchoalveolar lavage fluid and sputum from patients with lung cancer. Cancer Epidemiol. Biomark. Prev. 19:2665–72 [Google Scholar]
  217. Kolev M, Towner L, Donev R. 217.  2011. Complement in cancer and cancer immunotherapy. Arch. Immunol. Ther. Exp. 59:407–19 [Google Scholar]
  218. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A. 218.  et al. 2008. Modulation of the antitumor immune response by complement. Nat. Immunol. 9:1225–35 [Google Scholar]
  219. Vadrevu SK, Chintala NK, Sharma SK, Sharma P, Cleveland C. 219.  et al. 2014. Complement C5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 74:3454–65 [Google Scholar]
  220. Sohn JH, Bora PS, Suk HJ, Molina H, Kaplan HJ, Bora NS. 220.  2003. Tolerance is dependent on complement C3 fragment iC3b binding to antigen-presenting cells. Nat. Med. 9:206–12 [Google Scholar]
  221. Hsieh CC, Chou HS, Yang HR, Lin F, Bhatt S. 221.  et al. 2013. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121:1760–68 [Google Scholar]
  222. Gunn L, Ding C, Liu M, Ma Y, Qi C. 222.  et al. 2012. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J. Immunol. 189:2985–94 [Google Scholar]
  223. Strainic MG, Shevach EM, An F, Lin F, Medof ME. 223.  2013. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14:162–71 [Google Scholar]
  224. Laursen L. 224.  2011. E. coli crisis opens door for Alexion drug trial. Nat. Biotechnol. 29:671 [Google Scholar]
  225. Davis AE 3rd, Lu F, Mejia P. 225.  2010. C1 inhibitor, a multi-functional serine protease inhibitor. Thromb. Haemost. 104:886–93 [Google Scholar]
  226. Sacks SH, Zhou W. 226.  2012. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12:431–42 [Google Scholar]
  227. Lee YK, Mazmanian SK. 227.  2010. Has the microbiota played a critical role in the evolution of the adaptive immune system?. Science 330:1768–73 [Google Scholar]
  228. Hooper LV, Littman DR, Macpherson AJ. 228.  2012. Interactions between the microbiota and the immune system. Science 336:1268–73 [Google Scholar]
  229. Gagliani N, Hu B, Huber S, Elinav E, Flavell RA. 229.  2014. The fire within: microbes inflame tumors. Cell 157:776–83 [Google Scholar]
  230. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S. 230.  et al. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101 [Google Scholar]
  231. Grivennikov SI, Greten FR, Karin M. 231.  2010. Immunity, inflammation, and cancer. Cell 140:883–99 [Google Scholar]
  232. Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO. 232.  et al. 2011. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLOS Biol. 9:e1001212 [Google Scholar]
  233. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S. 233.  et al. 2010. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328:228–31 [Google Scholar]
  234. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA. 234.  et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–57 [Google Scholar]
  235. Hu B, Elinav E, Huber S, Strowig T, Hao L. 235.  et al. 2013. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. PNAS 110:9862–67 [Google Scholar]
  236. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A. 236.  et al. 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–33 [Google Scholar]
  237. Ivanov II, de Llanos Frutos R, Manel N, Yoshinaga K, Rifkin DB. 237.  et al. 2008. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–49 [Google Scholar]
  238. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T. 238.  et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–98 [Google Scholar]
  239. Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B. 239.  et al. 2012. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–58 [Google Scholar]
  240. Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F. 240.  et al. 2013. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210:917–31 [Google Scholar]
  241. Jiang R, Wang H, Deng L, Hou J, Shi R. 241.  et al. 2013. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13:59 [Google Scholar]
  242. Mazmanian SK, Round JL, Kasper DL. 242.  2008. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–25 [Google Scholar]
  243. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y. 243.  et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–36 [Google Scholar]
  244. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T. 244.  et al. 2012. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37:158–70 [Google Scholar]
  245. Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C. 245.  et al. 2012. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37:171–86 [Google Scholar]
  246. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N. 246.  et al. 2013. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:967–70 [Google Scholar]
  247. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R. 247.  et al. 2013. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–76 [Google Scholar]
  248. Drake CG, Lipson EJ, Brahmer JR. 248.  2014. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat. Rev. Clin. Oncol. 11:24–37 [Google Scholar]
  249. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM. 249.  et al. 1998. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med. 4:321–27 [Google Scholar]
  250. Peterson AC, Harlin H, Gajewski TF. 250.  2003. Immunization with Melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T-cell responses in advanced melanoma. J. Clin. Oncol. 21:2342–48 [Google Scholar]
  251. Fourcade J, Kudela P, Andrade Filho PA, Janjic B, Land SR. 251.  et al. 2008. Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J. Immunother. 31:781–91 [Google Scholar]
  252. Adams S, O'Neill DW, Nonaka D, Hardin E, Chiriboga L. 252.  et al. 2008. Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J. Immunol. 181:776–84 [Google Scholar]
  253. Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM. 253.  et al. 2012. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 72:1070–80 [Google Scholar]
  254. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y. 254.  et al. 2008. Predominant infiltration of macrophages and CD8+ T cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 113:1387–95 [Google Scholar]
  255. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B. 255.  et al. 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–64 [Google Scholar]
  256. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ. 256.  et al. 2011. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29:1949–55 [Google Scholar]
  257. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M. 257.  et al. 2003. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348:203–13 [Google Scholar]
  258. Grauer OM, Molling JW, Bennink E, Toonen LW, Sutmuller RP. 258.  et al. 2008. TLR ligands in the local treatment of established intracerebral murine gliomas. J. Immunol. 181:6720–29 [Google Scholar]
  259. Zou W, Zheng H, He TC, Chang J, Fu YX, Fan W. 259.  2012. LIGHT delivery to tumors by mesenchymal stem cells mobilizes an effective antitumor immune response. Cancer Res. 72:2980–89 [Google Scholar]
  260. Wang Y, Zhu M, Yu P, Fu YX. 260.  2010. Promoting immune responses by LIGHT in the face of abundant regulatory T cell inhibition. J. Immunol. 184:1589–95 [Google Scholar]
  261. Deng L, Liang H, Xu M, Yang X, Burnette B. 261.  et al. 2014. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–52 [Google Scholar]
  262. Spaapen RM, Leung MY, Fuertes MB, Kline JP, Zhang L. 262.  et al. 2014. Therapeutic activity of high-dose intratumoral IFN-beta requires direct effect on the tumor vasculature. J. Immunol. 193:4254–60 [Google Scholar]
  263. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D. 263.  et al. 2008. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14:28–36 [Google Scholar]
  264. Beatty GL. 264.  2011. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–16 [Google Scholar]
  265. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L. 265.  et al. 2010. CD4+ T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18:485–98 [Google Scholar]
  266. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L. 266.  et al. 2013. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38:729–41 [Google Scholar]
  267. Apetoh L. 267.  2007. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220:47–59 [Google Scholar]
  268. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C. 268.  et al. 2013. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19:1225–31 [Google Scholar]
  269. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM. 269.  et al. 2011. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17:1094–100 [Google Scholar]
  270. Burdelya L, Kujawski M, Niu G, Zhong B, Wang T. 270.  et al. 2005. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J. Immunol. 174:3925–31 [Google Scholar]
  271. Ugurel S, Schrama D, Keller G, Schadendorf D, Brocker EB. 271.  et al. 2008. Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol. Immunother. 57:685–91 [Google Scholar]

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