The split nature of tumor-infiltrating leukocytes: Implications for cancer surveillance and immunotherapy

OncoImmunology

Volumn 1, Issue 5, 2012, Pages 717-725

  Lança, Telma ^a   Silva Santos, Bruno ^a,b  

^a INSTITUTO DE MEDICINA MOLECULAR   (Portugal)

^b INSTITUTO GULBENKIAN DE CIÊNCIA   (Portugal)

Author keywords

Angiogenesis; Cytotoxicity; Interferon ; Prognostic marker; T helper cells; Tumor infiltrating lymphocyte

Indexed keywords

GAMMA INTERFERON; TRANSCRIPTION FACTOR FOXP3;

ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; CANCER EPIDEMIOLOGY; CANCER IMMUNOTHERAPY; CANCER PATIENT; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CYTOTOXIC T LYMPHOCYTE; HELPER CELL; HUMAN; MACROPHAGE; NATURAL KILLER CELL; NEUTROPHIL; NONHUMAN; PRIORITY JOURNAL; PROGNOSIS; REGULATORY T LYMPHOCYTE; REVIEW; TH1 CELL; TH17 CELL; TUMOR ASSOCIATED LEUKOCYTE; VALIDATION STUDY;

EID: 84879076366     PISSN: 21624011     EISSN: 2162402X     Source Type: Journal    
DOI: 10.4161/onci.20068     Document Type: Review

References (95)

1. Flavell RA, Sanjabi S, Wrzesinski SH, Limón-Licona P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 2010; 10:554-67; PMID:20616810; http://dx.doi.org/10. 1038/nri2808
2. Gomes AQ, Correia DV, Silva-Santos B. Non-classical major histocompatibility complex proteins as determinants of tumour immunosurveillance. EMBO Rep 2007; 8:1024-30; PMID:17972902; http://dx.doi.org/ 10.1038/sj.embor.7401090
3. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28:571-80; PMID:18394936; http://dx.doi.org/10.1016/j.immuni.2008.02.016
4. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011; 331:44-9; PMID:21212348; http://dx.doi.org/ 10.1126/science.1198687
5. Fregni G, Perier A, Avril MF, Caignard A. NK cells sense tumors, course of disease and treatments. OncoImmunology 2012; 1:38-47; http://dx.doi.org/ 10.4161/onci.1.1.18312
6. Ljunggren HG, Malmberg KJ. Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 2007; 7:329-39; PMID:17438573; http:// dx.doi.org/10.1038/nri2073
7. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res 2011; 71:5412-22; PMID:21708957; http://dx.doi.org/10. 1158/0008-5472.CAN-10-4179
8. Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 2011; 17:700-7; PMID:21552268; http://dx.doi.org/10.1038/nm.2366
9. Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet? Immunol Rev 2011; 239:27-44; PMID:21198663; http://dx.doi.org/10.1111/j.1600-065X.2010.00979.x
10. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Nat Rev Clin Oncol 2011; 8:577-85; PMID:21808266; http:// dx.doi.org/10.1038/nrclinonc.2011.116
11. Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med 2010; 207:1791-804; PMID:20660615; http://dx.doi. org/10.1084/jem.20092454
12. Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci U S A 2009; 106:17469-74; PMID: 19805141; http://dx.doi.org/10.1073/pnas.0907448106
13. Norell H, Zhang Y, McCracken J, Martins da Palma T, Lesher A, Liu Y, et al. CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting. Cancer Immunol Immunother 2010; 59:851-62; PMID:20052466; http://dx.doi.org/10.1007/s00262-009-0810-8
14. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725-33; PMID:21830940; http://dx.doi.org/10.1056/ NEJMoa1103849
15. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokineassociated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2011; PMID:22160384; http://dx.doi.org/10.1182/ blood-2011-10-384388
16. Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 2005; 54:721-8; PMID: 16010587; http://dx.doi.org/10.1007/s00262-004-0653-2
17. Takeshima T, Chamoto K, Wakita D, Ohkuri T, Togashi Y, Shirato H, et al. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res 2010; 70:2697-706; PMID:20215523; http://dx.doi.org/10.1158/0008-5472.CAN-09-2982
18. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 2009; 31:787-98; PMID:19879162; http://dx.doi.org/10.1016/j.immuni.2009.09.014
19. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 2009; 114:357-9; PMID:19289853; http://dx.doi.org/10.1182/blood-2008-09-177360
20. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008; 112:362-73; PMID:18354038; http://dx.doi.org/10. 1182/blood-2007-11-120998
21. Muranski P, Borman ZA, Kerkar SP, Klebanoff CA, Ji Y, Sanchez-Perez L, et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity 2011; 35:972-85; PMID:22177921; http://dx.doi.org/ 10.1016/j.immuni.2011.09.019
22. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 2009; 206: 1457-64; PMID:19564351; http://dx.doi.org/10. 1084/jem.20090207
23. Wang L, Yi T, Zhang W, Pardoll DM, Yu H. IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res 2010; 70:10112-20; PMID: 21159633; http://dx.doi.org/10.1158/0008-5472.CAN-10-0775
24. Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A 2010; 107:5540-4; PMID:20212110; http://dx.doi.org/10.1073/pnas.0912675107
25. Silva-Santos B. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing gammadelta T cells. Eur J Immunol 2010; 40:1873-6; PMID:20549671; http:// dx.doi.org/10.1002/eji.201040707
26. Lochner M, Peduto L, Cherrier M, Sawa S, Langa F, Varona R, et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 2008; 205:1381-93; PMID: 18504307; http://dx.doi.org/10.1084/jem.20080034
27. Wakita D, Sumida K, Iwakura Y, Nishikawa H, Ohkuri T, Chamoto K, et al. Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol 2010; 40:1927-37; PMID:20397212; http:// dx.doi.org/10.1002/eji.200940157
28. Ma Y, Aymeric L, Locher C, Mattarollo SR, Delahaye NF, Pereira P, et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med 2011; 208:491-503; PMID: 21383056; http://dx.doi.org/10.1084/jem.20100269
29. Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res 2011; 71:4809-20; PMID: 21646474; http://dx.doi.org/10.1158/0008-5472. CAN-11-0753
30. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science 2001; 294:605-9; PMID:11567106; http://dx.doi.org/10. 1126/science.1063916
31. Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 2003; 198:433-42; PMID:12900519; http://dx.doi.org/10.1084/jem.20030584
32. Street SE, Hayakawa Y, Zhan Y, Lew AM, MacGregor D, Jamieson AM, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J Exp Med 2004; 199: 879-84; PMID:15007091; http://dx.doi.org/10.1084/ jem.20031981
33. Liu Z, Eltoum IE, Guo B, Beck BH, Cloud GA, Lopez RD. Protective immunosurveillance and therapeutic antitumor activity of gammadelta T cells demonstrated in a mouse model of prostate cancer. J Immunol 2008; 180:6044-53; PMID:18424725
34. Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ, et al. CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17- producing gammadelta T cell subsets. Nat Immunol 2009; 10:427-36; PMID:19270712; http://dx.doi.org/ 10.1038/ni.1717
35. Gomes AQ, Martins DS, Silva-Santos B. Targeting cd T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application. Cancer Res 2010; 70:10024-7; PMID:21159627; http://dx.doi. org/10.1158/0008-5472.CAN-10-3236
36. Lança T, Correia DV, Moita CF, Raquel H, Neves- Costa A, Ferreira C, et al. The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/ lymphoma susceptibility to gammadelta T-cell cytotoxicity. Blood 2010; 115:2407-11; PMID:20101024; http://dx.doi.org/10.1182/blood-2009-08-237123
37. Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D, Silva-Santos B. Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 2011; 118:992-1001; PMID:21633088; http://dx.doi.org/10.1182/blood- 2011-02-339135
38. D'Cruz LM, Yang CY, Goldrath AW. Transcriptional regulation of NKT cell development and homeostasis. Curr Opin Immunol 2010; 22:199-205; PMID: 20171073; http://dx.doi.org/10.1016/j.coi.2010.01.014
39. Exley MA, Nakayama T. NKT-cell-based immunotherapies in clinical trials. Clin Immunol 2011; 140: 117-8; PMID:21592864; http://dx.doi.org/10.1016/j. clim.2011.04.015
40. Swann JB, Uldrich AP, van Dommelen S, Sharkey J, Murray WK, Godfrey DI, et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 2009; 113:6382-5; PMID:19234138; http://dx. doi.org/10.1182/blood-2009-01-198564
41. Terabe M, Swann J, Ambrosino E, Sinha P, Takaku S, Hayakawa Y, et al. A nonclassical non- Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med 2005; 202:1627-33; PMID: 16365146; http://dx.doi.org/10.1084/jem.20051381
42. Crowe NY, Coquet JM, Berzins SP, Kyparissoudis K, Keating R, Pellicci DG, et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med 2005; 202:1279-88; PMID:16275765; http://dx. doi.org/10.1084/jem.20050953
43. Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol 2011; 41:2522-5; PMID:21952810; http://dx.doi.org/ 10.1002/eji.201141894
44. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11:889-96; PMID: 20856220; http://dx.doi.org/10.1038/ni.1937
45. Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, et al. "Re-educating" tumorassociated macrophages by targeting NF-kappaB. J Exp Med 2008; 205:1261-8; PMID:18490490; http:// dx.doi.org/10.1084/jem.20080108
46. Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, et al. Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 2006; 116:2132-41; PMID:16862213; http://dx.doi.org/10. 1172/JCI27648
47. Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumorassociated macrophages. J Exp Med 2008; 205: 1673-85; PMID:18559453; http://dx.doi.org/10. 1084/jem.20072602
48. Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 2010; 24:241-55; PMID:20080943; http://dx.doi.org/10.1101/gad. 1874010
49. Houghton AM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 2010; 9:1732-7; PMID: 20404546; http://dx.doi.org/10.4161/cc.9.9.11297
50. Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 2010; 16:219-23; PMID:20081861; http:// dx.doi.org/10.1038/nm.2084
51. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141:52-67; PMID:20371345; http://dx.doi. org/10.1016/j.cell.2010.03.015
52. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 2009; 16:183-94; PMID:19732719; http://dx.doi.org/10.1016/j.ccr.2009.06.017
53. Piccard H, Muschel RJ, Opdenakker G. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 2011; PMID:21798756; http://dx.doi.org/10.1016/j. critrevonc.2011.06.004
54. Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S. Neutrophils responsive to endogenous IFNbeta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 2010; 120:1151-64; PMID:20237412; http://dx.doi.org/10.1172/JCI37223
55. Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 2011; 20:300-14; PMID:21907922; http://dx.doi.org/10. 1016/j.ccr.2011.08.012
56. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009; 182:4499-506; PMID:19342621; http://dx.doi.org/10.4049/jimmunol.0802740O
57. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32:19-25; PMID:21067974; http://dx.doi.org/10.1016/j.it.2010. 10.002
58. Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 2011; 9:e1001162; PMID:21980263; http://dx. doi.org/10.1371/journal.pbio.1001162
59. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010; 70:3052-61; PMID: 20388795; http://dx.doi.org/10.1158/0008-5472. CAN-09-3690
60. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010; 107:4275-80; PMID:20160101; http://dx.doi. org/10.1073/pnas.0915174107
61. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10:490-500; PMID: 20559327; http://dx.doi.org/10.1038/nri2785
62. Teng MW, Swann JB, von Scheidt B, Sharkey J, Zerafa N, McLaughlin N, et al. Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. Cancer Res 2010; 70:2665-74; PMID:20332236; http://dx.doi.org/10.1158/0008-5472.CAN-09-1574
63. Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? Lancet Oncol 2012; 13:e32-42; PMID:22225723; http://dx.doi.org/10.1016/S1470-2045(11)70155-3
64. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475:226-30; PMID:21753853; http:// dx.doi.org/10.1038/nature10169
65. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011; 470: 548-53; PMID:21326202; http://dx.doi.org/10.1038/ nature09707
66. Quezada SA, Peggs KS, Simpson TR, Allison JP. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication. Immunol Rev 2011; 241:104-18; PMID:21488893; http://dx.doi. org/10.1111/j.1600-065X.2011.01007.x
67. Fridman WH, Mlecnik B, Bindea G, Pagès F, Galon J. Immunosurveillance in human non-viral cancers. Curr Opin Immunol 2011; 23:272-8; PMID:21237631; http://dx.doi.org/10.1016/j.coi.2010.12.011
68. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 2011; 208:1949-62; PMID:21930770; http://dx. doi.org/10.1084/jem.20101956
69. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 2011; 71:5678-87; PMID: 21846823; http://dx.doi.org/10.1158/0008-5472. CAN-11-0431
70. Ladoire S, Arnould L, Mignot G, Apetoh L, Rébé C, Martin F, et al. T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival. Br J Cancer 2011; 105:366-71; PMID:21750556; http://dx.doi.org/10.1038/bjc.2011. 261
71. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012; 61:427-38; PMID:21930732; http://dx.doi.org/10.1136/ gutjnl-2011-300509
72. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:2586-93; PMID:17577038; http://dx.doi.org/10.1200/JCO. 2006.09.4565
73. Chen KJ, Zhou L, Xie HY, Ahmed TE, Feng XW, Zheng SS. Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med Oncol 2011; PMID:21678026; http://dx.doi.org/10.1007/ s12032-011-0006-x
74. Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010; 59:653-61; PMID:19908042; http://dx.doi.org/ 10.1007/s00262-009-0781-9
75. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010; 33:435-41; PMID:20386463; http://dx.doi.org/10.1097/CJI. 0b013e3181d32f01
76. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NelH, et al. Prognostic value of tumorinfiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12:465-72; PMID:16428488; http://dx.doi.org/10.1158/1078-0432.CCR-05-1886
77. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011; 60:909-18; PMID:21644034; http://dx.doi.org/10.1007/s00262-011-1046-y
78. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 2008; 93:193-200; PMID: 18223287; http://dx.doi.org/10.3324/haematol.11702
79. Kim WY, Jeon YK, Kim TM, Kim JE, Kim YA, Lee SH, et al. Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma. Ann Oncol 2009; 20:1688-96; PMID:19542249; http://dx.doi.org/10.1093/annonc/ mdp056
80. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 2011; 208: 469-78; PMID:21339327; http://dx.doi.org/10.1084/jem.20101876
81. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostateinfiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 2008; 14:3254-61; PMID: 18519750; http://dx.doi.org/10.1158/1078-0432. CCR-07-5164
82. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009; 50:980-9; PMID:19329213; http:// dx.doi.org/10.1016/j.jhep.2008.12.033
83. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009; 114:1141-9; PMID:19470694; http://dx.doi.org/10.1182/blood-2009-03-208249
84. Lv L, Pan K, Li XD, She KL, Zhao JJ, Wang W, et al. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One 2011; 6:e18219; PMID: 21483813; http://dx.doi.org/10.1371/journal.pone. 0018219
85. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011; 71:1263-71; PMID:21303976; http://dx.doi.org/10.1158/0008-5472.CAN-10-2907
86. Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009; 27:5944-51; PMID:19858404; http://dx.doi.org/10.1200/JCO. 2008.19.6147
87. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 29:610-8; PMID:21245428; http://dx.doi.org/10. 1200/JCO.2010.30.5425
88. Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res 2003; 63:1555-9; PMID:12670904
89. Schumacher K, Haensch W, Röefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 2001; 61:3932-6; PMID:11358808
90. Raspollini MR, Castiglione F, Rossi Degl'innocenti D, Amunni G, Villanucci A, Garbini F, et al. Tumourinfiltrating gamma/delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma. Ann Oncol 2005; 16:590-6; PMID: 15699022; http://dx.doi.org/10.1093/annonc/mdi112
91. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942-9; PMID:15322536; http://dx.doi.org/10.1038/nm1093
92. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006; 24:5373-80; PMID:17135638; http://dx.doi.org/10. 1200/JCO.2006.05.9584
93. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin- 13. Cancer Immunol Immunother 2011; 60:1419-30; PMID:21644036; http://dx.doi.org/10.1007/s00262-011-1028-0
94. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 2012; 65:159-63; PMID:22049225; http://dx.doi.org/ 10.1136/jclinpath-2011-200355
95. Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 2009; 27:4709-17; PMID:19720929; http://dx.doi. org/10.1200/JCO.2008.18.9498