Tumor infiltrating lymphocytes in gastrointestinal tumors: Controversies and future clinical implications

Critical Reviews in Oncology/Hematology

Volumn 110, Issue , 2017, Pages 106-116

  Solinas, Cinzia ^a   Pusole, Grazia ^b   Demurtas, Laura ^b   Puzzoni, Marco ^b   Mascia, Roberta ^b   Morgan, Gilberto ^c   Giampieri, Riccardo ^d   Scartozzi, Mario ^b  

^a UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

^b UNIVERSITY OF CAGLIARI   (Italy)

^c LUND UNIVERSITY HOSPITAL   (Sweden)

^d UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

Author keywords

Gastrointestinal tumors; Immunotherapy; Microsatellite instability; Prognosis; Tumor infiltrating lymphocytes

Indexed keywords

ANTINEOPLASTIC AGENT; CD8 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 22; IPILIMUMAB; NIVOLUMAB; PEMBROLIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; TICILIMUMAB; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TUMOR MARKER; TUMOR NECROSIS FACTOR;

ADAPTIVE IMMUNITY; ADJUVANT THERAPY; ANUS CANCER; AUTOIMMUNE DISEASE; B LYMPHOCYTE; BILIARY TRACT CANCER; BILIARY TRACT SURGERY; CANCER ADJUVANT THERAPY; CANCER CELL; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CD8+ T LYMPHOCYTE; CHRONIC INFLAMMATION; COLORECTAL CANCER; COLORECTAL SURGERY; CYTOKINE RELEASE; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; DISEASE FREE SURVIVAL; ENVIRONMENTAL FACTOR; HUMAN; IMMUNE RESPONSE; IMMUNOTHERAPY; INFECTION; INHIBITION KINETICS; INNATE IMMUNITY; LIVER CELL CARCINOMA; LIVER SURGERY; METASTASIS POTENTIAL; METASTATIC MELANOMA; MICROSATELLITE INSTABILITY; NATURAL KILLER CELL; NON SMALL CELL LUNG CANCER; OVERALL SURVIVAL; PANCREAS CANCER; PANCREAS RESECTION; PHASE 2 CLINICAL TRIAL (TOPIC); PREDICTION; PROGRESSION FREE SURVIVAL; REGULATORY T LYMPHOCYTE; REVIEW; STOMACH CANCER; STOMACH SURGERY; TUMOR ASSOCIATED LEUKOCYTE; TUMOR GROWTH; TUMOR MICROENVIRONMENT; ANIMAL; CHEMISTRY; GASTROINTESTINAL NEOPLASMS; IMMUNOLOGY; PROGNOSIS;

ANIMALS; BIOMARKERS, TUMOR; GASTROINTESTINAL NEOPLASMS; HUMANS; IMMUNOTHERAPY; LYMPHOCYTES, TUMOR-INFILTRATING; PROGNOSIS;

EID: 85010206860     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2016.11.016     Document Type: Review

References (100)

1. Amedei, A., Niccolai, E., Benagiano, M., Bella, C.D., Cianchi, F., Bechi, P., et al. Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. Cancer. Immunol. Immunother. 62 (2013), 1249–1260, 10.1007/s00262-013-1429-3.
2. Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.-M., Gingras, M.-C., et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531 (2016), 47–52, 10.1038/nature16965.
3. Bendell, J.C., Kim, T.W., Goh, B.C., Wallin, J., Oh, D.-Y., Han, S.-W., et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J. Clin. Oncol., 34, 2016.
4. Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D.R., Steins, M., Ready, N.E., et al. Nivolumab versus Docetaxel in advanced nonsquamous non–small–cell lung cancer. N. Engl. J. Med. 373 (2015), 1627–1639, 10.1056/NEJMoa1507643.
5. Cabrera, R., Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma. Oncol. Rep., 2013, 10.3892/or.2013.2290.
6. Cancer Res, Cancer Statistics for the UK. 2015, Cancer Res, UK http://www.cancerresearchuk.org/health-professional/cancer-statistics (accessed May 21, 2016).
7. Chen, X., Du, Y., Lin, X., Qian, Y., Zhou, T., Huang, Z., CD4 + CD25 + regulatory T cells in tumor immunity. Int. Immunopharmacol. 34 (2016), 244–249, 10.1016/j.intimp.2016.03.009.
8. Chiaravalli, A.M., Feltri, M., Bertolini, V., Bagnoli, E., Furlan, D., Cerutti, R., et al. Intratumour T. cells, their activation status and survival in gastric carcinomas characterised for microsatellite instability and Epstein-Barr virus infection. Virchows Arch. 448 (2005), 344–353, 10.1007/s00428-005-0066-4.
9. Choi, H.S., Ha, S.Y., Kim, H.-M., Ahn, S.M., Kang, M.-S., Kim, K.-M., et al. The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients. Oncotarget 7 (2016), 7940–7951.
10. Churlaud, G., Pitoiset, F., Jebbawi, F., Lorenzon, R., Bellier, B., Rosenzwajg, M., et al. Human and mouse CD8 + CD25 + FOXP3+ regulatory T cells at steady state and during interleukin-2 therapy. T Cell Biol, 6, 2015, 171, 10.3389/fimmu.2015.00171.
11. Cutsem, E.V., Cervantes, A., Nordlinger, B., Arnold, D., Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25 (2014), iii1–iii9, 10.1093/annonc/mdu260.
12. Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J., Schreiber, R.D., Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3 (2002), 991–998, 10.1038/ni1102-991.
13. Eggermont, A.M.M., Chiarion-Sileni, V., Grob, J.-J., Dummer, R., Wolchok, J.D., Schmidt, H., et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med., 2016, 10.1056/nejmoa1611299.
14. Farazi, P.A., DePinho, R.A., Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer. 6 (2006), 674–687, 10.1038/nrc1934.
15. Ferris, R.L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A.D., Licitra, L., et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med., 2016, 10.1056/nejmoa1602252.
16. Fridman, W.H., Pagès, F., Sautès-Fridman, C., Galon, J., The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12 (2012), 298–306, 10.1038/nrc3245.
17. Fukunaga, A., Miyamoto, M., Cho, Y., Murakami, S., Kawarada, Y., Oshikiri, T., et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28 (2004), e26–31.
18. Gabitass, R.F., Annels, N.E., Stocken, D.D., Pandha, H.A., Middleton, G.W., 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. 60 (2011), 1419–1430, 10.1007/s00262-011-1028-0.
19. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313 (2006), 1960–1964, 10.1126/science.1129139.
20. Galon, J., Pagès, F., Marincola, F.M., Thurin, M., Trinchieri, G., Fox, B.A., et al. The immune score as a new possible approach for the classification of cancer. J. Transl. Med., 10, 2012, 1, 10.1186/1479-5876-10-1.
21. Gao, Q., Qiu, S.-J., Fan, J., Zhou, J., Wang, X.-Y., Xiao, Y.-S., et al. Intratumoral balance of regulatory and cytotoxic t cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol. 25 (2007), 2586–2593, 10.1200/JCO.2006.09.4565.
22. Garnelo, M., Tan, A., Her, Z., Yeong, J., Lim, C.J., Chen, J., et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut, 2015, 10.1136/gutjnl-2015-310814 gutjnl-2015-310814.
23. Giampieri, R., Maccaroni, E., Mandolesi, A., Prete, M.D., Andrikou, K., Faloppi, L., et al. Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy. Gastric Cancer 2016 (2016), 1–8, 10.1007/s10120-016-0594-4.
24. Giannakis, M., Mu, X.J., Shukla, S.A., Qian, Z.R., Cohen, O., Nishihara, R., et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15 (2016), 857–865, 10.1016/j.celrep.2016.03.075.
25. Gilbert, D.C., Serup-Hansen, E., Linnemann, D., Høgdall, E., Bailey, C., Summers, J., et al. Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer. Br. J. Cancer 114 (2016), 134–137, 10.1038/bjc.2015.448.
26. Glaire, M.A., Domingo, E., Vermeulen, L., Wezel van, T., Liefers, G.-J., Lothe, R.A., et al. POLE proofreading domain mutation defines a subset of immunogenic colorectal cancers with excellent prognosis. Ann. Oncol., 27, 2016, 10.1093/annonc/mdw370.09 460O.
27. Goeppert, B., Frauenschuh, L., Zucknick, M., Stenzinger, A., Andrulis, M., Klauschen, F., et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br. J. Cancer 109 (2013), 2665–2674, 10.1038/bjc.2013.610.
28. Gorosito Serrán, M., Fiocca Vernengo, F., Beccaria, C.G., Acosta Rodriguez, E.V., Montes, C.L., Gruppi, A., The regulatory role of B cells in autoimmunity, infections and cancer: perspectives beyond IL10 production. FEBS Lett. 589 (2015), 3362–3369, 10.1016/j.febslet.2015.08.048.
29. Grabenbauer, G.G., Lahmer, G., Distel, L., Niedobitek, G., Tumor-infiltrating cytotoxic T. cells but not regulatory cells predict outcome in anal squamous cell carcinoma. Clin. Cancer Res. 12 (2006), 3355–3360, 10.1158/1078-0432.CCR-05-2434.
30. Gregory, A.D., Houghton, A.M., Tumor-associated neutrophils new targets for cancer therapy. Cancer Res. 71 (2011), 2411–2416, 10.1158/0008-5472 CAN-10-2583.
31. Grivennikov, S.I., Greten, F.R., Karin, M., IMmunity, inflammation, and cancer. Cell 140 (2010), 883–899, 10.1016/j.cell.2010.01.025.
32. Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21 (2015), 1350–1356, 10.1038/nm.3967.
33. Haas, M., Dimmler, A., Hohenberger, W., Grabenbauer, G.G., Niedobitek, G., Distel, L.V., Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroentero.l, 9, 2009, 65, 10.1186/1471-230X-9-65.
34. Hadjipanayis, Angela, The cancer genome atlas research network comprehensive molecular characterization of gastric adenocarcinoma. Nature 513 (2014), 202–209, 10.1038/nature13480.
35. Hiraoka, N., Ino, Y., Yamazaki-Itoh, R., Kanai, Y., Kosuge, T., Shimada, K., Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112 (2015), 1782–1790, 10.1038/bjc.2015.145.
36. Hoff, D.D.V., Ramanathan, R.K., Borad, M.J., Laheru, D.A., Smith, L.S., Wood, T.E., et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29 (2011), 4548–4554, 10.1200/JCO.2011.36.5742.
37. Hou, J., Yu, Z., Xiang, R., Li, C., Wang, L., Chen, S., et al. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp. Mol. Pathol. 96 (2014), 284–291, 10.1016/j.yexmp.2014.03.005.
38. Hu, M., Li, K., Maskey, N., Xu, Z., Peng, C., Wang, B., et al. Decreased intratumoral Foxp3 Tregs and increased dendritic cell density by neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer. Int. J. Clin. Exp. Pathol. 7 (2014), 4685–4694.
39. Hu, W.-H., Miyai, K., Cajas-Monson, L.C., Luo, L., Liu, L., Ramamoorthy, S.L., Tumor-infiltrating CD8+ T lymphocytes associated with clinical outcome in anal squamous cell carcinoma. J. Surg. Oncol. 112 (2015), 421–426, 10.1002/jso.23998.
40. Huang, Y., Liao, H., Zhang, Y., Yuan, R., Wang, F., Gao, Y., et al. Prognostic value of tumor-infiltrating foxP3 + T Cells in gastrointestinal cancers: a meta analysis. PLoS One, 9, 2014, e94376, 10.1371/journal.pone.0094376.
41. Hwang, W.-T., Adams, S.F., Tahirovic, E., Hagemann, I.S., Coukos, G., Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol. Oncol. 124 (2012), 192–198, 10.1016/j.ygyno.2011.09.039.
42. Ikeguchi, M., Hirooka, Y., Interleukin-2 gene expression is a new biological prognostic marker in hepatocellular carcinomas. Onkologie 28 (2005), 255–259, 10.1159/000084695.
43. Ishii, Y., Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis: implications for cholangiocarcinogenesis. Int. J. Oncol., 2013, 10.3892/ijo.2013.2038.
44. Janjigian, Y.Y., Sanchez-Vega, F., Jonsson, P., Tuvy, Y., Bouvier, N., Riches, J., et al. Clinical next generation sequencing (NGS) of esophagogastric (EG) adenocarcinomas identifies distinct molecular signatures of response to HER2 inhibition, first-line 5FU/platinum and PD1/CTLA4 blockade. Ann. Oncol., 27, 2016, 612O, 10.1093/annonc/mdw371.04.
45. Kang, B.W., Seo, A.N., Yoon, S., Bae, H.I., Jeon, S.W., Kwon, O.K., et al. Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. Ann. Oncol. 27 (2016), 494–501, 10.1093/annonc/mdv610.
46. Kim, J.W., Nam, K.H., Ahn, S.-H., Park, D.J., Kim, H.-H., Kim, S.H., et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric. Cancer. 19 (2014), 42–52, 10.1007/s10120-014-0440-5.
47. Kim, S.Y., Park, C., Kim, H.-J., Park, J., Hwang, J., Kim, J.-I., et al. Deregulation of immune response genes in patients with epstein-barr virus-associated gastric cancer and outcomes. Gastroenterology 148 (2015), 137–147, 10.1053/j.gastro.2014.09.020 e9.
48. Kim, J., Bae, J.-S., Kim, J., Bae, J.-S., Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediat. Inflamm. Mediat. Inflamm., 2016, 2016, 10.1155/2016/6058147 2016:e6058147.
49. Kumar, V., Patel, S., Tcyganov, E., Gabrilovich, D.I., The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37 (2016), 208–220, 10.1016/j.it.2016.01.004.
50. Ladoire, S., Martin, F., Ghiringhelli, F., Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol. Immunother. 60 (2011), 909–918, 10.1007/s00262-011-1046-y.
51. Lal, N., Beggs, A.D., Willcox, B.E., Middleton, G.W., An immunogenomic stratification of colorectal cancer: Implications for development of targeted immunotherapy. OncoImmunology, 4, 2015, e976052, 10.4161/2162402X.2014.76052.
52. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373 (2015), 23–34, 10.1056/NEJMoa1504030.
53. Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D., et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372 (2015), 2509–2520, 10.1056/NEJMoa1500596.
54. Li, K., Zhu, Z., Luo, J., Fang, J., Zhou, H., Hu, M., et al. Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer. Int. J. Clin. Exp. Pathol. 8 (2015), 14725–14732.
55. Lin, G., Liu, Y., Li, S., Mao, Y., Wang, J., Shuang, Z., et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget, 5, 2016.
56. Liu, K., Yang, K., Wu, B., Chen, H., Chen, X., Chen, X., et al. Tumor-infiltrating immune cells are associated with prognosis of gastric cancer. Medicine (Baltimore), 94, 2015, 10.1097/MD.0000000000001631.
57. Llovet, J.M., Villanueva, A., Lachenmayer, A., Finn, R.S., Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol., 12, 2015, 436, 10.1038/nrclinonc.2015.121.
58. Lutz, E.R., Wu, A.A., Bigelow, E., Sharma, R., Mo, G., Soares, K., et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res 2 (2014), 616–631, 10.1158/2326-6066.CIR-14-0027.
59. McGranahan, N., Furness, A.J.S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S.K., et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351 (2016), 1463–1469, 10.1126/science.aaf1490.
60. Melero, I., Sangro, B., Yau, T., Hsu, C., Kudo, M., Crocenzi, T., et al. Safety and preliminary efficacy of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (aHCC): Interim analysis of the phase 1/2 CheckMate-040 study. Ann. Oncol., 27, 2016, 615O, 10.1093/annonc/mdw371.07.
61. Mlecnik, B., Bindea, G., Angell, H.K., Maby, P., Angelova, M., Tougeron, D., et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44 (2016), 698–711, 10.1016/j.immuni.2016.02.025.
62. Morris, M., Platell, C., Iacopetta, B., Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. Clin. Cancer Res. 14 (2008), 1413–1417, 10.1158/1078-0432.CCR-07-1994.
63. Morris, M., Platell, C., de Boer, B., McCaul, K., Iacopetta, B., Population-based study of prognostic factors in stage II colonic cancer. Br. J. Surg. 93 (2008), 866–871, 10.1002/bjs.5345.
64. Motzer, R.J., Escudier, B., McDermott, D.F., George, S., Hammers, H.J., Srinivas, S., et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373 (2015), 1803–1813, 10.1056/NEJMoa1510665.
65. NCCN, Clinical Practice Guidelines in Oncology n.d. 2017 (accessed May 21, 2016) https://www.nccn.org/professionals/physician_gls/f_guidelines_nojava.asp.
66. Naito, Y., Saito, K., Shiiba, K., Ohuchi, A., Saigenji, K., Nagura, H., et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58 (1998), 3491–3494.
67. Ng, S.S.W., Tsao, M.-S., Nicklee, T., Hedley, D.W., Effects of the epidermal growth factor receptor inhibitor OSI-774, tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol. Cancer Ther. 1 (2002), 777–778 1 Supported by the National Cancer Institute of Canada and the Pat Myhal Fund for Pancreatic Cancer Research 1.
68. Niccolai, E., Taddei, A., Ricci, F., Rolla, S., D'Elios, M.M., Benagiano, M., et al. Intra-tumoral IFN-(-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer. Clin. Sci. 130 (2016), 247–258, 10.1042/CS20150437.
69. Oshikiri, T., Miyamoto, M., Shichinohe, T., Suzuoki, M., Hiraoka, K., Nakakubo, Y., et al. Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J. Surg. Oncol. 84 (2003), 224–228, 10.1002/jso.10321.
70. Overman, M.J., Kopetz, S., McDermott, R.S., Leach, J., Lonardi, S., Lenz, H.-J., et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate -142 interim results. J. Clin. Oncol., 34, 2016.
71. 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. 27 (2009), 5944–5951, 10.1200/JCO. 2008.19.6147.
72. Prall, F., Dührkop, T., Weirich, V., Ostwald, C., Lenz, P., Nizze, H., et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum. Pathol. 35 (2004), 808–816, 10.1016/j.humpath.2004.01.022.
73. Reck, M., Rodríguez-Abreu, D., Robinson, A.G., Hui, R., Csőszi, T., Fülöp, A., et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med., 2016, 10.1056/NEJMoa1606774.
74. Reissfelder, C., Stamova, S., Gossmann, C., Braun, M., Bonertz, A., Walliczek, U., et al. Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J. Clin. Invest. 125 (2015), 739–751, 10.1172/JCI74894.
75. Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J., et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348 (2015), 124–128, 10.1126/science.aaa1348.
76. Rosenberg, J.E., Hoffman-Censits, J., Powles, T., van der Heijden, M.S., Balar, A.V., Necchi, A., et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387 (2016), 1909–1920, 10.1016/S0140-6736(16)00561-4.
77. Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G., et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26 (2015), 259–271, 10.1093/annonc/mdu450.
78. Sangro, B., Gomez-Martin, C., de la Mata, M., Iñarrairaegui, M., Garralda, E., Barrera, P., et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59 (2013), 81–88, 10.1016/j.jhep.2013.02.022.
79. Shao, Y., Lo, C.M., Ling, C.C., Liu, X.B., Ng, K.T.-P., Chu, A.C.Y., Regulatory, B., et al. cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett. 355 (2014), 264–272, 10.1016/j.canlet.2014.09.026.
80. Shen, Z., Zhou, S., Wang, Y., Li, R., Zhong, C., Liang, C., et al. Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J. Cancer Res. Clin. Oncol. 136 (2010), 1585–1595, 10.1007/s00432-010-0816-9.
81. Shinto, E., Hase, K., Hashiguchi, Y., Sekizawa, A., Ueno, H., Shikina, A., et al. CD8+ and FOXP3+ Tumor-infiltrating T. cells before and after chemoradiotherapy for rectal cancer. Ann. Surg. Oncol. 21 (2014), 414–421, 10.1245/s10434-014-3584-y.
82. Shirabe, K., Matsumata, T., Maeda, T., Sadanaga, N., Kuwano, H., Sugimachi, K., A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration–a clinicopathological study. Hepatogastroenterology 42 (1995), 996–1001.
83. Siliņa, K., Rulle, U., Kalniņa, Z., Linē, A., Manipulation of tumour-infiltrating B cells and tertiary lymphoid structures: a novel anti-cancer treatment avenue?. Cancer Immunol. Immunother. 63 (2014), 643–662, 10.1007/s00262-014-1544-9.
84. Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J.M., Desrichard, A., et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371 (2014), 2189–2199, 10.1056/NEJMoa1406498.
85. Thomas, N.E., Busam, K.J., From, L., Kricker, A., Armstrong, B.K., Anton-Culver, H., et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma Study. J. Clin. Oncol. 31 (2013), 4252–4259, 10.1200/JCO. 2013.51.3002.
86. Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, I.P., Taylor, E.J.M., Robert, L., et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515 (2014), 568–571, 10.1038/nature13954.
87. Unitt, E., Rushbrook, S.M., Marshall, A., Davies, S., Gibbs, P., Morris, L.S., et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41 (2005), 722–730, 10.1002/hep.20644.
88. Vivier, E., Ugolini, S., Blaise, D., Chabannon, C., Brossay, L., Targeting natural killer cells and natural killer T cells in cancer. Nat. Rev. Immunol. 12 (2012), 239–252, 10.1038/nri3174.
89. Volovitz, I., Melzer, S., Amar, S., Bocsi, J., Bloch, M., Efroni, S., et al. Dendritic cells in the context of human tumors: biology and experimental tools. Int. Rev. Immunol. 35 (2016), 116–135, 10.3109/08830185.2015.1096935.
90. WHO, Cancer. 2016, WHO n.d. http://www.who.int/mediacentre/factsheets/fs297/en/(accessed 2016).
91. Wada, Y., Nakashima, O., Kutami, R., Yamamoto, O., Kojiro, M., Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 27 (1998), 407–414, 10.1002/hep.510270214.
92. Wang, D., Liu, Y., Gu, Y., Qin, Y., Ji, H., Wu, L., et al. Increased number of forkhead box P3+ tumor-infiltrating lymphocytes correlates with high preoperative albumin level and better survival in patients with stage II or III colorectal cancer. Tumor. Biol. 36 (2015), 5407–5414, 10.1007/s13277-015-3206-8.
93. Wang, L., Zhai, Z.-W., Ji, D.-B., Li, Z.-W., Gu, J., Prognostic value of CD45RO(+) tumor-infiltrating lymphocytes for locally advanced rectal cancer following 30 Gy/10f neoadjuvant radiotherapy. Int. J. Colorectal Dis. 30 (2015), 753–760, 10.1007/s00384-015-2226-6.
94. Wang, Y., Liu, T., Tang, W., Deng, B., Chen, Y., Zhu, J., Hepatocellular Carcinoma Cells Induce Regulatory, T., et al. Cells and lead to poor prognosis via production of transforming growth factor-?1. Cell Physiol. Biochem. 38 (2016), 306–318, 10.1159/000438631.
95. Yamashita, Y.-I., Taketomi, A., Morita, K., Fukuhara, T., Ueda, S., Sanefuji, K., et al. The impact of surgical treatment and poor prognostic factors for patients with intrahepatic cholangiocarcinoma: retrospective analysis of 60 patients. Anticancer Res. 28 (2008), 2353–2359.
96. Ye, Y., Zhou, L., Xie, X., Jiang, G., Xie, H., Zheng, S., Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J. Surg. Oncol. 100 (2009), 500–504, 10.1002/jso.21376.
97. Zeng, D.-Q., Yu, Y.-F., Ou, Q.-Y., Li, X.-Y., Zhong, R.-Z., Xie, C.-M., et al. Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer. Oncotarget, 2016, 10.18632/oncotarget.7282.
98. Zhang, L., Qiu, M., Jin, Y., Ji, J., Li, B., Wang, X., et al. Programmed cell death ligand 1 (PD-L1) expression on gastric cancer and its relationship with clinicopathologic factors. Int. J. Clin. Exp. Pathol. 8 (2015), 11084–11091.
99. Zhou, S., Xu, S., Tao, H., Zhen, Z., Chen, G., Zhang, Z., et al. CCR7 Expression and Intratumoral FOXP3 + Regulatory T Cells are Correlated with Overall Survival and Lymph Node Metastasis in Gastric Cancer. PLoS One, 8, 2013, e74430, 10.1371/journal.pone.0074430.
100. Zitvogel, L., Tesniere, A., Apetoh, L., Ghiringhelli, F., Kroemer, G., Immunological aspects of anticancer chemotherapy. Bull. Académie Natl. Méd., 192, 2008 1469-1487-1489.