Innate immune recognition of cancer

Annual Review of Immunology

Volumn 33, Issue , 2015, Pages 445-474

  Woo, Seng Ryong ^a   Corrales, Leticia ^a   Gajewski, Thomas F ^a,b  

^a UNIVERSITY OF CHICAGO   (United States)

^b UNIVERSITY OF CHICAGO   (United States)

Author keywords

Cancer immunotherapy; Innate immune sensing; STING; Tumor immunity; Type I interferons

Indexed keywords

ADENOSINE TRIPHOSPHATE; CALRETICULIN; COMPLEMENT; HIGH MOBILITY GROUP B1 PROTEIN; INTERFERON; LIGAND; NUCLEIC ACID;

ANTIGEN PRESENTING CELL; ANTIGEN RECOGNITION; ARTICLE; CANCER CELL; CANCER IMMUNOTHERAPY; CELL ACTIVATION; CELL POPULATION; COMPLEMENT ACTIVATION; DENDRITIC CELL; GAMMA DELTA T LYMPHOCYTE; HUMAN; INNATE IMMUNITY; LYMPHOID CELL; MACROPHAGE; MACROPHAGE ACTIVATION; MICROFLORA; NATURAL KILLER CELL; NATURAL KILLER T CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN SECRETION; TUMOR ASSOCIATED LEUKOCYTE; TUMOR IMMUNITY; ANIMAL; CYTOLOGY; CYTOTOXICITY; IMMUNE SYSTEM; IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MICROBIOLOGY; NEOPLASMS; SIGNAL TRANSDUCTION;

ANIMALS; ANTIGEN-PRESENTING CELLS; COMPLEMENT SYSTEM PROTEINS; CYTOTOXICITY, IMMUNOLOGIC; DENDRITIC CELLS; HUMANS; IMMUNE SYSTEM; IMMUNITY, INNATE; IMMUNOTHERAPY; LIGANDS; MACROPHAGE ACTIVATION; MACROPHAGES; MICROBIOTA; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84927585373     PISSN: 07320582     EISSN: 15453278     Source Type: Book Series    
DOI: 10.1146/annurev-immunol-032414-112043     Document Type: Article

References (271)

1. Boon T, Gajewski TF,Coulie PG. 1995. From defined human tumor antigens to effective immunization? Immunol. Today 16:334-36
2. Valmori D, Scheibenbogen C, Dutoit V, Nagorsen D, Asemissen AM, et al. 2002. Circulating tumorreactive CD8+ T cells in melanoma patients contain a CD45RA+CCR7- effector subset exerting ex vivo tumor-specific cytolytic activity. Cancer Res. 62:1743-50
3. Harlin H, Meng Y, Peterson AC, Zha Y, TretiakovaM, et al. 2009. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69:3077-85
4. Speiser DE, Baumgaertner P, Barbey C, Rubio-Godoy V, Moulin A, 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
5. Anichini A,Molla A, Mortarini R, Tragni G, Bersani I, 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
6. Wang X, Yu J, Sreekumar A, Varambally S, Shen R, et al. 2005. Autoantibody signatures in prostate cancer. N. Engl. J. Med. 353:1224-35
7. Robbins PF, Lu YC, El-Gamil M, Li YF,Gross C, et al. 2013. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19:747-52
8. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, et al. 2013. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31:e439-42
9. Kvistborg P, van Buuren MM, Schumacher TN. 2013. Human cancer regression antigens. Curr. Opin. Immunol. 25:284-90
10. MarkiewiczMA,GajewskiTF. 1999. The immunesystem as anti-tumor sentinel:molecular requirements for an anti-tumor immune response. Crit. Rev. Oncog. 10:247-60
11. Gajewski TF, Louahed J, Brichard VG. 2010. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16:399-403
12. Gajewski TF, Schreiber H, Fu YX. 2013. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14:1014-22
13. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, 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
14. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. 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
15. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, et al. 2012. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61:1019-31
16. HamidO, Schmidt H, Nissan A,Ridolfi L, Aamdal S, et al. 2011. A prospective phase II trial exploring the association between tumormicroenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9:204
17. Joseph RW, Eckel-Passow JE, Sharma R, Liu P, Parker A, et al. 2012. Characterizing the clinical benefit of ipilimumab in patients who progressed on high-dose IL-2. J. Immunother. 35:711-15
18. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443-54
19. Ascierto ML, Idowu MO, Zhao Y, Khalak H, Payne KK, 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
20. Tachibana T, Onodera H, Tsuruyama T,Mori A,Nagayama S, et al. 2005. Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin. Cancer Res. 11:7322-27
21. Ma C, Zhang Q, Ye J, Wang F, Zhang Y, et al. 2012. Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. J. Immunol. 189:5029-36
22. Diefenbach A, Colonna M, Koyasu S. 2014. Development, differentiation, and diversity of innate lymphoid cells. Immunity 41:354-65
23. Coca S, Perez-Piqueras J,MartinezD,Colmenarejo A, Saez MA, et al. 1997. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79:2320-28
24. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, et al. 2000. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88:577-83
25. Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, 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
26. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, et al. 2008. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571-80
27. Mishra R, Chen AT,Welsh RM, Szomolanyi-Tsuda E. 2010.NKcells and γδT cells mediate resistance to polyomavirus-induced tumors. PLOS Pathog. 6:e1000924
28. Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. 2005. NKG2D function protects the host from tumor initiation. J. Exp. Med. 202:583-88
29. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, et al. 2000. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191:661-68
30. Smyth MJ, Crowe NY, Godfrey DI. 2001. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13:459-63
31. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, 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
32. Masson D, Jarry A, Baury B, Blanchardie P, Laboisse C, et al. 2001. Overexpression of the CD155 gene in human colorectal carcinoma. Gut 49:236-40
33. Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, 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
34. Iguchi-Manaka A, Kai H, Yamashita Y, Shibata K, Tahara-Hanaoka S, et al. 2008. Accelerated tumor growth in mice deficient in DNAM-1 receptor. J. Exp. Med. 205:2959-64
35. Liu XV, Ho SS, Tan JJ, Kamran N, Gasser S. 2012. Ras activation induces expression of Raet1 family NK receptor ligands. J. Immunol. 189:1826-34
36. Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH. 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
37. Gasser S, Orsulic S, Brown EJ, Raulet DH. 2005. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186-90
38. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, et al. 2009. ATM-ATR-dependent upregulation 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
39. Ardolino M, Zingoni A, Cerboni C, Cecere F, Soriani A, 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
40. Lord CJ, Ashworth A. 2012. The DNA damage response and cancer therapy. Nature 481:287-94
41. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, et al. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864-70
42. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, et al. 2005. Activation of theDNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907-13
43. Waldhauer I, Steinle A. 2008. NK cells and cancer immunosurveillance. Oncogene 27:5932-43
44. Liu RB, Engels B, Arina A, Schreiber K, Hyjek E, et al. 2012. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res. 72:1964-74
45. ChengM, Chen Y, Xiao W, Sun R, Tian Z. 2013.NKcell-based immunotherapy for malignant diseases. Cell Mol. Immunol. 10:230-52
46. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, et al. 2004. Induced recruitment of NK cells to lymph nodes provides IFN-γfor TH1 priming. Nat. Immunol. 5:1260-65
47. Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, 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
48. Kelly JM, Darcy PK,Markby JL, Godfrey DI, Takeda K, et al. 2002. Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat. Immunol. 3:83-90
49. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. 2013. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31:413-41
50. Groh V,WuJ, YeeC, Spies T. 2002. Tumour-derived solubleMIC ligands impair expression ofNKG2D and T-cell activation. Nature 419:734-38
51. JinushiM, Takehara T, Tatsumi T, Hiramatsu N, Sakamori R, 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
52. Nuckel H, Switala M, Sellmann L, Horn PA, Durig J, et al. 2010. The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. Leukemia 24:1152-59
53. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, et al. 2014. Recognition of tumors by the innate immune system and natural killer cells. Adv. Immunol. 122:91-128
54. Coudert JD, Scarpellino L, Gros F, Vivier E, Held W. 2008. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 111:3571-78
55. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, et al. 2002. Defective expression and function of natural killer cell-triggering receptors in patientswith acute myeloid leukemia. Blood 99:3661-67
56. Crome SQ, Lang PA, Lang KS, Ohashi PS. 2013. Natural killer cells regulate diverse T cell responses. Trends Immunol. 34:342-49
57. Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, et al. 2011. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat. Med. 17:700-7
58. Zhang T, Lemoi BA, Sentman CL. 2005. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106:1544-51
59. Barber A, Rynda A, Sentman CL. 2009. Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J. Immunol. 183:6939-47
60. JinushiM,Hodi FS,Dranoff G. 2006. Therapy-induced antibodies toMHCclass I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. PNAS 103:9190-95
61. Lam AR, Le Bert N, Ho SS, Shen YJ, Tang ML, et al. 2014. RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res. 74:2193-203
62. CroweNY, Smyth MJ, Godfrey DI. 2002. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med. 196:119-27
63. Swann JB, Uldrich AP, van Dommelen S, Sharkey J, Murray WK, et al. 2009. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113:6382-85
64. Lantz O, Bendelac A. 1994. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp.Med. 180:1097-106
65. Bendelac A. 1995. CD1 recognition by mouse NK1+ T lymphocytes. Science 268:863-65
66. Kawano T. 1997. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626-29
67. Zhou D. 2004. Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786-89
68. Mannik LA, Chin-Yee I, Sharif S, Van Kaer L, Delovitch TL, Haeryfar SM. 2011. Engagement of glycosylphosphatidylinositol-anchored proteins results in enhanced mouse and human invariant natural killer T cell responses. Immunology 132:361-75
69. Joyce S,Woods AS, Yewdell JW, Bennink JR,De Silva AD, et al. 1998. Natural ligand ofmouse CD1d1: cellular glycosylphosphatidylinositol. Science 279:1541-44
70. Wu DY, Segal NH, Sidobre S, Kronenberg M, Chapman PB. 2003. Cross-presentation of disialoganglioside GD3 to natural killer T cells. J. Exp. Med. 198:173-81
71. Ambrosino E, Terabe M, Halder RC, Peng J, Takaku S, et al. 2007. Cross-regulation between type I and type IINKTcells in regulating tumor immunity: a new immunoregulatory axis. J. Immunol. 179:5126-36
72. Berzofsky JA, Terabe M. 2008. A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity. Cancer Immunol. Immunother. 57:1679-83
73. Matsuda JL,Mallevaey T, Scott-Browne J, Gapin L. 2008. CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Curr. Opin. Immunol. 20:358-68
74. Raghuraman G, Geng Y, Wang CR. 2006. IFN-beta-mediated up-regulation of CD1d in bacteriainfected APCs. J. Immunol. 177:7841-48
75. Van Kaer L, Parekh VV, Wu L. 2011. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res. 343:43-55
76. Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM. 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
77. Parekh VV, Wilson MT, Olivares-Villagomez D, Singh AK, Wu L, et al. 2005. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115:2572-83
78. Terabe M, Berzofsky JA. 2008. The role ofNKT cells in tumor immunity. Adv. Cancer Res. 101:277-348
79. Moreno M, Molling JW, von Mensdorff-Pouilly S, Verheijen RH, Hooijberg E, et al. 2008. IFNgamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. J. Immunol. 181:2446-54
80. Shimizu K, Mizuno T, Shinga J, Asakura M, Kakimi K, 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
81. Richter J, Neparidze N, Zhang L, Nair S, Monesmith T, et al. 2013. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423-30
82. Gehrmann U, Hiltbrunner S,Georgoudaki AM, KarlssonMC, Naslund TI, Gabrielsson S. 2013. Synergistic induction of adaptive antitumor immunity by codelivery of antigen with alpha-galactosylceramide on exosomes. Cancer Res. 73:3865-76
83. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, et al. 2000. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat. Immunol. 1:515-20
84. Corvaisier M, Moreau-Aubry A, Diez E, Bennouna J, Mosnier JF, et al. 2005. Vγ9Vδ2 T cell response to colon carcinoma cells. J. Immunol. 175:5481-88
85. Liu Z, Guo BL, Gehrs BC, Nan L, Lopez RD. 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
86. Viey E, Fromont G, Escudier B, Morel Y, Da Rocha S, et al. 2005. Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma. J. Immunol. 174:1338-47
87. Burjanadze M, Condomines M, Reme T, Quittet P, Latry P, et al. 2007. In vitro expansion of gamma deltaTcells with anti-myeloma cell activity by Phosphostim and IL-2 in patients withmultiplemyeloma. Br. J. Haematol. 139:206-16
88. Saitoh A, Narita M, Watanabe N, TochikiN, Satoh N, et al. 2008. Anti-tumor cytotoxicity of γδT cells expanded from peripheral blood cells of patients with myeloma and lymphoma. Med. Oncol. 25:137-47
89. KabelitzD,Wesch D, Pitters E, ZollerM. 2004. Characterization of tumor reactivity of human Vγ9Vδ2 γδT cells in vitro and in SCID mice in vivo. J. Immunol. 173:6767-76
90. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, et al. 2001. Regulation of cutaneous malignancy by γδT cells. Science 294:605-9
91. Mattarollo SR, Kenna T, Nieda M, Nicol AJ. 2007. Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity. Cancer Immunol. Immunother. 56:1285-97
92. Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G. 2003. Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 197:163-68
93. Chien YH, Konigshofer Y. 2007. Antigen recognition by γδT cells. Immunol. Rev. 215:46-58
94. Scotet E. 2005. Tumor recognition following Vγ9Vδ2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71-80
95. Luoma AM, Castro CD, Mayassi T, Bembinster LA, Bai L, 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
96. Thedrez A. 2007. Self/non-self discrimination by human γδTcells: simple solutions for a complex issue? Immunol. Rev. 215:123-35
97. Raulet DH, Guerra N. 2009. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat. Rev. Immunol. 9:568-78
98. Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K, 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
99. Tokuyama H, Hagi T, Mattarollo SR, Morley J, Wang Q, 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
100. Do JS, Min B. 2009. IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and γδT cells in vivo. Blood 113:6361-71
101. Marcu-Malina V,Heijhuurs S, van Buuren M, Hartkamp L, Strand S, et al. 2011. Redirecting αβT cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor. Blood 118:50-59
102. Martinet L, Fleury-Cappellesso S, Gadelorge M, Dietrich G, Bourin P, et al. 2009. A regulatory crosstalk between Vγ9Vδ2 T lymphocytes and mesenchymal stem cells. Eur. J. Immunol. 39:752-62
103. Kunzmann V, Kimmel B, Herrmann T, Einsele H, Wilhelm M. 2009. Inhibition of phosphoantigenmediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells. Immunology 126:256-67
104. Martinet L, Poupot R, Fournie JJ. 2009. Pitfalls on the roadmap to γδT cell-based cancer immunotherapies. Immunol. Lett. 124:1-8
105. Peng G. 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
106. Di Carlo E, Bocca P, Emionite L, Cilli M, Cipollone G, 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
107. Kobayashi H, Tanaka Y, Nakazawa H, Yagi J, Minato N, Tanabe K. 2011. A new indicator of favorable prognosis in locally advanced renal cell carcinomas: γδ T-cells in peripheral blood. Anticancer Res. 31:1027-31
108. Fisher JP, Heuijerjans J, YanM, Gustafsson K, Anderson J. 2014. γδT cells for cancer immunotherapy: a systematic review of clinical trials. Oncoimmunology 3:e27572
109. Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G. 2007. Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J. Immunol. 178:1534-41
110. den Haan JM, Lehar SM, Bevan MJ. 2000. CD8+ but not CD8- dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192:1685-96
111. Villadangos JA, Schnorrer P. 2007. Intrinsic and cooperative antigen-presenting functions of dendriticcell subsets in vivo. Nat. Rev. Immunol. 7:543-55
112. LiuC, Lou Y, LizeeG,Qin H, Liu S, et al. 2008. Plasmacytoid dendritic cells induceNKcell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J. Clin. Investig. 118:1165-75
113. Wei S, Kryczek I, Zou L, Daniel B, Cheng P, et al. 2005. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65:5020-26
114. Labidi-Galy SI, Treilleux I, Goddard-Leon S, Combes JD, Blay JY, et al. 2012. Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis. Oncoimmunology 1:380-82
115. Demoulin S, Herfs M, Delvenne P, Hubert P. 2013. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J. Leukoc. Biol. 93:343-52
116. Sisirak V, Faget J, Gobert M, Goutagny N, Vey N, 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
117. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. 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
118. Watkins SK. 2011. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J. Clin. Investig. 121:1361-72
119. Sancho D, Mourao-Sa D, Joffre OP, Schulz O, Rogers NC, et al. 2008. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Investig. 118:2098-110
120. Ahrens S. 2012. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36:635-45
121. Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D, et al. 2009. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458:899-903
122. Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, et al. 2010. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells. J. Exp. Med. 207:1261-71
123. Crozat K, Guiton R, Contreras V, Feuillet V, Dutertre CA, 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
124. Hildner K, Edelson BT, PurthaWE, Diamond M, Matsushita H, et al. 2008. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322:1097-100
125. Fuertes MB, Kacha AK, Kline J,Woo SR, Kranz DM, 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
126. Bingle L, Brown NJ, Lewis CE. 2002. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196:254-65
127. Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, et al. 2005. Tumor-associated macrophages: the doubleedged sword in cancer progression. J. Clin. Oncol. 23:953-64
128. Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA. 2008. Increased density of tumorassociated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr. Relat. Cancer 15:1069-74
129. Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, et al. 2010. An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70:1323-33
130. Medrek C, Ponten F, Jirstrom K, Leandersson K. 2012. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer 12:306
131. Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI, 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
132. ZhangQW, Liu L,Gong CY, Shi HS, Zeng YH, et al. 2012. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLOS One 7:e50946
133. Chitu V, Stanley ER. 2006. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18:39-48
134. Mantovani A, Savino B, LocatiM, Zammataro L, Allavena P, Bonecchi R. 2010. The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev. 21:27-39
135. Hagemann T, Wilson J, Burke F,Kulbe H, Li NF, et al. 2006. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol. 176:5023-32
136. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, 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
137. Lin EY, Nguyen AV, Russell RG, Pollard JW. 2001. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193:727-40
138. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, et al. 2011. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222-325
139. Mantovani A, Allavena P, Sica A, Balkwill F. 2008. Cancer-related inflammation. Nature 454:436-44
140. Kessenbrock K, Plaks V,Werb Z. 2010. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52-67
141. Lin EY. 2006. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66:11238-46
142. Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, 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
143. KuangDM. 2009. Activatedmonocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206:1327-37
144. Torroella-KouriM. 2009. Identification of a subpopulation ofmacrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res. 69:4800-9
145. Curiel TJ. 2004. Specific recruitment of regulatoryTcells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10:942-49
146. DeNardo DG. 2009.CD4+Tcells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91-102
147. Duluc D, CorvaisierM, Blanchard S, Catala L, Descamps P, 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
148. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. 2005. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65:3437-46
149. Wang YC, He F, Feng F, Liu XW, Dong GY, et al. 2010. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70:4840-49
150. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, et al. 2012. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. PNAS 109:17561-66
151. Gonzalez-Navajas JM, Lee J,David M, Raz E. 2012. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12:125-35
152. Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF. 2013. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34:67-73
153. Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, et al. 2011. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208:1989-2003
154. Devilder MC, Allain S, Dousset C, Bonneville M, Scotet E. 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
155. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, et al. 2008. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14:299-311
156. Yang X, Zhang X, FuML, Weichselbaum RR, Gajewski TF, et al. 2014. Targeting the tumor microenvironment with interferon-beta bridges innate and adaptive immune responses. Cancer Cell 25:37-48
157. Burnette BC, LiangH, Lee Y, Chlewicki L,KhodarevNN, et al. 2011. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 71:2488-96
158. Swann JB, Hayakawa Y, Zerafa N, Sheehan KC, Scott B, et al. 2007. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J. Immunol. 178:7540-49
159. U'Ren L, Guth A, Kamstock D, Dow S. 2010. Type I interferons inhibit the generation of tumorassociated macrophages. Cancer Immunol. Immunother. 59:587-98
160. Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, et al. 2014. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42
161. Barbalat R, Ewald SE,Mouchess ML, BartonGM. 2011. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29:185-214
162. Kono H, Rock KL. 2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8:279-89
163. Rathinam VA, Fitzgerald KA. 2011. Cytosolic surveillance and antiviral immunity. Curr. Opin. Virol. 1:455-62
164. Crow MK. 2007. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316:359-86
165. Reich CF 3rd, Pisetsky DS. 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
166. YoshidaH,Okabe Y, Kawane K, Fukuyama H, Nagata S. 2005. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6:49-56
167. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. 2000. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25:177-81
168. Green DR, Ferguson T, Zitvogel L, Kroemer G. 2009. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9:353-63
169. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. 2013. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31:51-72
170. ObeidM. 2007. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13:54-61
171. Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. 2011. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71:4809-20
172. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. 2012. The emergence of phox-ER stress induced immunogenic apoptosis. OncoImmunology 1:787-89
173. Dudek AM, Garg AD, Krysko DV,De RuysscherD, Agostinis P. 2013. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev. 24:319-33
174. Garg AD. 2012. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31:1062-79
175. Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, et al. 2008. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 15:3-12
176. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. 2012. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12:860-75
177. Garg AD. 2010. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim. Biophys. Acta 1805:53-71
178. Muller S, Ronfani L, Bianchi ME. 2004. Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J. Intern. Med. 255:332-43
179. Apetoh L. 2007. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13:1050-59
180. Jube S. 2012. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 72:3290-301
181. Yang GL. 2012. Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer. J. Surg. Oncol. 106:57-61
182. Chiba S. 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
183. Venereau E. 2012. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209:1519-28
184. Yang H. 2012. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol. Med. 18:250-59
185. MacLennan DH, Yip CC, Iles GH, Seeman P. 1972. Isolation of sarcoplasmic reticulum proteins. Cold Spring Harb. Symp. Quant. Biol. 37:469-77
186. Obeid M, Tesniere A, Panaretakis T, Tufi R, Joza N, et al. 2007. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220:22-34
187. Miyamoto S. 2012. Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma. Cancer Res. 72:2609-21
188. Gardai SJ. 2005. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through transactivation of LRP on the phagocyte. Cell 123:321-34
189. Pawaria S, Binder RJ. 2011. CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat. Commun. 2:521
190. Panaretakis T. 2009. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28:578-90
191. Wemeau M, Kepp O, Tesniere A, Panaretakis T, Flament C, 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
192. Peng RQ, Chen YB, Ding Y, Zhang R, Zhang X, et al. 2010. Expression of calreticulin is associated with infiltration of T-cells in stage IIIB colon cancer. World J. Gastroenterol. 16:2428-34
193. Martins I. 2009. Chemotherapy induces ATP release from tumor cells. Cell Cycle 8:3723-28
194. Michaud M. 2011. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334:1573-77
195. Martins I. 2012. Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy 8:413-15
196. Elliott MR. 2009. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282-86
197. Ghiringhelli F. 2009. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15:1170-78
198. Mortensen SP, Thaning P, Nyberg M, Saltin B, Hellsten Y. 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
199. Robson SC, Sevigny J, Zimmermann H. 2006. The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal. 2:409-30
200. Beavis PA, Stagg J, Darcy PK, Smyth MJ. 2012. CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 33:231-37
201. Stagg J. 2012. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72:2190-96
202. Ohta A. 2006. A2A adenosine receptor protects tumors from antitumor T cells. PNAS 103:13132-37
203. Markiewski MM, Lambris JD. 2009. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 30:286-92
204. Walport MJ. 2001. Complement. N. Engl. J. Med. 344:1058-66
205. Ricklin D, Hajishengallis G, Yang K, Lambris JD. 2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11:785-97
206. Gasque P, Thomas A, FontaineM,Morgan BP. 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
207. Lucas SD, Karlsson-Parra A, Nilsson B, Grimelius L, Akerstrom G, et al. 1996. Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Hum. Pathol. 27:1329-35
208. Niculescu F, Rus HG, Retegan M, Vlaicu R. 1992. Persistent complement activation on tumor cells in breast cancer. Am. J. Pathol. 140:1039-43
209. Ajona D, Pajares MJ, Corrales L, Perez-Gracia JL, Agorreta J, 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
210. Bjorge L, Hakulinen J, Vintermyr OK, Jarva H, Jensen TS, et al. 2005. Ascitic complement system in ovarian cancer. Br. J. Cancer 92:895-905
211. Corrales L, Ajona D, Rafail S, Lasarte JJ, Riezu-Boj JI, et al. 2012. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J. Immunol. 189:4674-83
212. Ytting H, Christensen IJ, Thiel S, Jensenius JC, Nielsen HJ. 2005. Serum mannan-binding lectinassociated serine protease 2 levels in colorectal cancer: relation to recurrence and mortality. Clin. Cancer Res. 11:1441-46
213. Jurianz K, Ziegler S, Garcia-SchulerH, Kraus S, Bohana-Kashtan O, et al. 1999. Complement resistance of tumor cells: basal and induced mechanisms. Mol. Immunol. 36:929-39
214. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. 2003. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol. Immunol. 40:109-23
215. GanczD, Fishelson Z. 2009. Cancer resistance to complement-dependent cytotoxicity (CDC): problemoriented research and development. Mol. Immunol. 46:2794-800
216. Pio R, Garcia J, Corrales L, Ajona D, Fleischhacker M, 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
217. KolevM,Towner L,Donev R. 2011. Complement in cancer and cancer immunotherapy. Arch. Immunol. Ther. Exp. 59:407-19
218. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, et al. 2008. Modulation of the antitumor immune response by complement. Nat. Immunol. 9:1225-35
219. Vadrevu SK, Chintala NK, Sharma SK, Sharma P, Cleveland C, et al. 2014. Complement C5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 74:3454-65
220. Sohn JH,BoraPS, SukHJ, MolinaH,Kaplan HJ,BoraNS. 2003. Tolerance is dependent on complement C3 fragment iC3b binding to antigen-presenting cells. Nat. Med. 9:206-12
221. Hsieh CC, Chou HS, Yang HR, Lin F, Bhatt S, et al. 2013. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood 121:1760-68
222. Gunn L, Ding C, Liu M, Ma Y, Qi C, et al. 2012. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J. Immunol. 189:2985-94
223. Strainic MG, Shevach EM, An F, Lin F, Medof ME. 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
224. Laursen L. 2011. E. coli crisis opens door for Alexion drug trial. Nat. Biotechnol. 29:671
225. Davis AE 3rd, Lu F, Mejia P. 2010. C1 inhibitor, a multi-functional serine protease inhibitor. Thromb. Haemost. 104:886-93
226. Sacks SH, Zhou W. 2012. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12:431-42
227. Lee YK, Mazmanian SK. 2010. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330:1768-73
228. Hooper LV, Littman DR, Macpherson AJ. 2012. Interactions between the microbiota and the immune system. Science 336:1268-73
229. Gagliani N, Hu B, Huber S, Elinav E, Flavell RA. 2014. The fire within: microbes inflame tumors. Cell 157:776-83
230. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, et al. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97-101
231. Grivennikov SI, Greten FR, Karin M. 2010. Immunity, inflammation, and cancer. Cell 140:883-99
232. Caricilli AM, Picardi PK, deAbreu LL, Ueno M, Prada PO, et al. 2011. Gutmicrobiota is a keymodulator of insulin resistance in TLR 2 knockout mice. PLOS Biol. 9:e1001212
233. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, et al. 2010. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor. Science 328:228-31
234. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745-57
235. Hu B, Elinav E, Huber S, Strowig T, Hao L, et al. 2013. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. PNAS 110:9862-67
236. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121-33
237. Ivanov II, de Llanos Frutos R, Manel N, Yoshinaga K, Rifkin DB, 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
238. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485-98
239. Grivennikov SI, Wang K, MucidaD, Stewart CA, Schnabl B, et al. 2012. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254-58
240. Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, et al. 2013. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210:917-31
241. Jiang R, Wang H, Deng L, Hou J, Shi R, et al. 2013. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13:59
242. Mazmanian SK, Round JL, Kasper DL. 2008. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620-25
243. Atarashi K, Tanoue T, OshimaK, Suda W, Nagano Y, et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232-36
244. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, et al. 2012. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37:158-70
245. Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C, et al. 2012. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37:171-86
246. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, et al. 2013. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:967-70
247. Viaud S, Saccheri F,MignotG, Yamazaki T,Daillere R, et al. 2013. The intestinalmicrobiotamodulates the anticancer immune effects of cyclophosphamide. Science 342:971-76
248. Drake CG, Lipson EJ, Brahmer JR. 2014. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat. Rev. Clin. Oncol. 11:24-37
249. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, 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
250. Peterson AC, Harlin H, Gajewski TF. 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
251. Fourcade J, Kudela P, Andrade Filho PA, Janjic B, Land SR, 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
252. Adams S, O'Neill DW, Nonaka D, Hardin E, Chiriboga L, 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
253. ErdagG, Schaefer JT, SmolkinME, DeaconDH, Shea SM, 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
254. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, 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
255. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, et al. 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960-64
256. Mahmoud SM, Paish EC, Powe DG, Macmillan RD,Grainge MJ, et al. 2011. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29:1949-55
257. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, et al. 2003. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348:203-13
258. Grauer OM,Molling JW, Bennink E, Toonen LW, Sutmuller RP, et al. 2008. TLR ligands in the local treatment of established intracerebral murine gliomas. J. Immunol. 181:6720-29
259. Zou W, Zheng H, He TC, Chang J, Fu YX, FanW. 2012. LIGHT delivery to tumors by mesenchymal stem cells mobilizes an effective antitumor immune response. Cancer Res. 72:2980-89
260. Wang Y, ZhuM, Yu P, Fu YX. 2010. Promoting immune responses by LIGHT in the face of abundant regulatory T cell inhibition. J. Immunol. 184:1589-95
261. Deng L, Liang H, Xu M, Yang X, Burnette B, et al. 2014. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843-52
262. Spaapen RM, Leung MY, Fuertes MB, Kline JP, Zhang L, et al. 2014. Therapeutic activity of high-dose intratumoral IFN-beta requires direct effect on the tumor vasculature. J. Immunol. 193:4254-60
263. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, 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
264. Beatty GL. 2011. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612-16
265. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, 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
266. MaY, Adjemian S, Mattarollo SR,YamazakiT,Aymeric L, et al. 2013. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38:729-41
267. Apetoh L. 2007. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220:47-59
268. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, 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
269. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, et al. 2011. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 17:1094-100
270. Burdelya L, Kujawski M, Niu G, Zhong B, Wang T, 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
271. Ugurel S, SchramaD, KellerG, SchadendorfD, Brocker EB, et al. 2008. Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol. Immunother. 57:685-91