S. L. Topalian, J. M. Taube, R. A. Anders, and D. M. Pardoll, Mechanismdriven biomarkers to guide immune checkpoint blockade in cancer therapy, Nat Rev Cancer, vol.16, issue.5, pp.275-287, 2016.

, , p.27079802

H. Ghebeh, S. Mohammed, A. Al-omair, A. Qattan, C. Lehe et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors, Neoplasia, vol.8, issue.3, 2006.

C. Wu, Y. Zhu, J. Jiang, J. Zhao, X. G. Zhang et al., Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance, Acta Histochem, vol.108, issue.1, pp.19-24, 2006.


J. Hamanishi, M. Mandai, M. Iwasaki, T. Okazaki, Y. Tanaka et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer, Proc Natl Acad Sci, vol.104, issue.9, pp.3360-3365, 2007.

, , p.17360651

T. Nomi, M. Sho, T. Akahori, K. Hamada, A. Kubo et al., Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer, Clin Cancer Res, vol.13, issue.7, pp.2151-2157, 2007.

, , p.17404099

V. Velcheti, K. A. Schalper, D. E. Carvajal, V. K. Anagnostou, K. N. Syrigos et al., Programmed death ligand-1 expression in non-small cell lung cancer, Lab Invest, vol.94, issue.1, p.24217091, 2014.

M. M. Gubin, X. Zhang, H. Schuster, C. E. Ward, J. P. Noguchi et al., Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens, Nature, vol.515, issue.7528, p.25428507, 2014.

C. Linnemann, M. M. Van-buuren, L. Bies, E. M. Verdegaal, R. Schotte et al., High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma, Nat Med, vol.21, issue.1, 2015.

N. A. Rizvi, M. D. Hellmann, A. Snyder, P. Kvistborg, V. Makarov et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, vol.348, issue.6230, 2015.

N. J. Llosa, M. Cruise, A. Tam, E. C. Wicks, E. M. Hechenbleikner et al., vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints, Cancer Discov, vol.5, issue.1, p.25358689, 2015.

B. Mlecnik, G. Bindea, H. K. Angell, P. Maby, M. Angelova et al., Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability, Immunity, vol.44, issue.3, 2016.

D. T. Le, J. N. Uram, H. Wang, B. R. Bartlett, H. Kemberling et al., PD-1 blockade in tumors with mismatch-repair deficiency, N Engl J Med, vol.372, issue.26, 2015.

M. J. Overman, R. Mcdermott, J. L. Leach, S. Lonardi, H. J. Lenz et al., Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study, Lancet Oncol, vol.18, issue.9, pp.30422-30431, 2017.

V. Shankaran, H. Ikeda, A. T. Bruce, J. M. White, P. E. Swanson et al., IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity, Nature, vol.410, issue.6832, 2001.

H. Ikeda, L. J. Old, and R. D. Schreiber, The roles of IFN gamma in protection against tumor development and cancer immunoediting, Cytokine Growth Factor Rev, vol.13, issue.2, p.11900986, 2002.

G. P. Dunn, H. Ikeda, A. T. Bruce, C. Koebel, R. Uppaluri et al., Interferongamma and cancer immunoediting, Immunol Res, vol.32, p.16106075, 2005.

D. Ostroumov, N. Fekete-drimusz, M. Saborowski, F. Kühnel, and N. Woller, CD4 and CD8 T lymphocyte interplay in controlling tumor growth, Cell Mol Life Sci, vol.75, issue.4, 2018.

J. Galon, A. Costes, F. Sanchez-cabo, A. Kirilovsky, B. Mlecnik et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, Science, vol.313, issue.5795, 2006.

M. Tosolini, A. Kirilovsky, B. Mlecnik, T. Fredriksen, S. Mauger 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, vol.71, issue.4, 2011.

K. Abiko, N. Matsumura, J. Hamanishi, N. Horikawa, R. Murakami et al., IFN-? from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer, Br J Cancer, vol.112, issue.9, 2015.

R. Bellucci, A. Martin, D. Bommarito, K. Wang, S. H. Hansen et al., Interferon-?-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression, Oncoimmunology, vol.4, issue.6, 2015.

S. Spranger, R. M. Spaapen, Y. Zha, J. Williams, Y. Meng et al., Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells, Sci Transl Med, vol.5, 0200.

R. S. Herbst, J. C. Soria, M. Kowanetz, G. D. Fine, O. Hamid et al., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients, Nature, vol.515, issue.7528, pp.563-567, 2014.

L. Fehrenbacher, A. Spira, M. Ballinger, M. Kowanetz, J. Vansteenkiste et al., Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial, Lancet, vol.387, 2016.

M. Ayers, J. Lunceford, M. Nebozhyn, E. Murphy, A. Loboda et al., IFN-?-related mRNA profile predicts clinical response to PD-1 blockade, J Clin Invest, vol.127, issue.8, 2017.

N. Karachaliou, M. Gonzalez-cao, G. Crespo, A. Drozdowskyj, E. Aldeguer et al., Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients, Ther Adv Med Oncol, vol.10, 2018.

S. J. Szabo, S. T. Kim, G. L. Costa, X. Zhang, C. G. Fathman et al., A novel transcription factor, T-bet, directs Th1 lineage commitment, Cell, vol.100, issue.6, p.10761931, 2000.

B. M. Sullivan, A. Juedes, S. J. Szabo, M. Von-herrath, and L. H. Glimcher, Antigen-driven effector CD8 T cell function regulated by T-bet, Proc Natl Acad Sci U S A, vol.100, issue.26, 2003.

J. Liu, A. Hamrouni, D. Wolowiec, V. Coiteux, K. Kuliczkowski et al., Plasma cells from multiple myeloma patients express B7-H1 (PD-L1)and increase expression after stimulation with IFNgamma and TLR ligands via a MyD88, TRAF6-, and MEK-dependent pathway, Blood, vol.110, issue.1, p.17363736, 2007.

S. Gordon, Alternative activation of macrophages, Nat Rev Immunol, vol.3, issue.1, 2003.
URL : https://hal.archives-ouvertes.fr/hal-00474829

S. Gordon and F. O. Martinez, Alternative activation of macrophages: mechanism and functions, Immunity, vol.32, issue.5, 2010.

M. J. Overman, S. Lonardi, K. Wong, H. J. Lenz, F. Gelsomino et al., Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer, J Clin Oncol, vol.36, issue.8, 2018.

D. T. Le, P. Kavan, T. W. Kim, M. E. Burge, E. V. Cutsem et al., Pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer, J Clin Oncol, vol.36, p.3514, 2018.

N. L. De-vries, M. Swets, A. L. Vahrmeijer, M. Hokland, and P. J. Kuppen, The Immunogenicity of colorectal cancer in relation to tumor development and treatment, Int J Mol Sci, vol.17, issue.7, 2016.

J. A. Keene and K. Forman, Helper activity is required for the in vivo generation of cytotoxic T cells, J Exp Med, vol.155, p.6801178, 1982.

L. Yo-ping, J. Chung-jiuan, and C. Shu-ching, The roles of CD4+ T cells in tumor immunity, ISRN Immunology, vol.497397, 2011.

S. A. Quezada, T. R. Simpson, K. S. Peggs, T. Merghoub, J. Vider et al., Tumorreactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts, J Exp Med, vol.207, issue.3, 2010.

L. Marisa, M. Svrcek, A. Collura, E. Becht, P. Cervera et al., The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors, J Natl Cancer Inst, vol.110, issue.1, p.28922790, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01727817

F. Boissière-michot, G. Lazennec, H. Frugier, M. Jarlier, L. Roca et al., Characterization of an adaptive immune response in microsatellite-instable colorectal cancer, Oncoimmunology, vol.3, 2014.

A. Ling, I. V. Lundberg, V. Eklöf, M. L. Wikberg, Å. Öberg et al., The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer

, J Pathol Clin Res, vol.2, issue.1, 2015.

M. W. Teng, S. F. Ngiow, A. Ribas, and M. J. Smyth, Classifying cancers based on T-cell infiltration and PD-L1, Cancer Res, vol.75, issue.11, 2015.

D. S. Chen and I. Mellman, Elements of cancer immunity and the cancer-immune set point, Nature, vol.541, issue.7637, 2017.

A. Ribas, C. Robert, F. S. Hodi, J. D. Wolchok, A. M. Joshua et al., Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature, J Clin Oncol, vol.33, 2015.

J. H. Kim, H. E. Park, N. Y. Cho, H. S. Lee, and G. H. Kang, Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers, Br J Cancer, vol.115, issue.4, p.27404452, 2009.

L. H. Lee, M. S. Cavalcanti, N. H. Segal, J. F. Hechtman, M. R. Weiser et al., Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma, Mod Pathol, vol.29, issue.11, 2016.

M. W. Rosenbaum, J. R. Bledsoe, V. Morales-oyarvide, T. G. Huynh, and M. Mino-kenudson, PDL1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes, Mod Pathol, vol.29, issue.9, 2016.

S. Inaguma, J. Lasota, Z. Wang, A. Felisiak-golabek, H. Ikeda et al., Clinicopathologic profile, immunophenotype, and genotype of CD274(PD-L1)-positive colorectal carcinomas, Mod Pathol, vol.30, issue.2, p.27813511, 2017.

S. Korehisa, E. Oki, M. Iimori, Y. Nakaji, M. Shimokawa et al., Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability, Int J Cancer, vol.142, issue.4, 2018.

A. M. Valentini, D. Pinto, F. Cariola, F. Guerra, V. Giannelli et al., PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments, Oncotarget, vol.9, issue.9, p.29492219, 2018.

J. M. Taube, R. A. Anders, G. D. Young, H. Xu, R. Sharma et al., Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape, Sci Transl Med, vol.4, issue.127, 2012.

W. Zhang, Q. Pang, C. Yan, Q. Wang, J. Yang et al., Induction of PD-L1 expression by epidermal growth factor receptor-mediated signaling in esophageal squamous cell carcinoma, Onco Targets Ther, vol.10, 2017.

X. Jiang, J. Zhou, A. Giobbie-hurder, J. Wargo, and F. S. Hodi, The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition, Clin Cancer Res, vol.19, issue.3, p.23095323, 2013.

K. Friedman, A. S. Brodsky, S. Lu, S. Wood, A. J. Gill et al., Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment, Mod Pathol, vol.29, issue.5, pp.528-541, 2016.


A. Engin, I. I. Gonul, A. B. Engin, A. Karamercan, S. Dincel et al., Relationship between indoleamine 2,3-dioxygenase activity and lymphatic invasion propensity of colorectal carcinoma, World J Gastroenterol, vol.22, issue.13, p.27053851, 2016.

S. Y. Chon, H. H. Hassanain, and S. L. Gupta, Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene, J Biol Chem, vol.271, issue.29, p.8663541, 1996.

O. Takikawa, A. Habara-ohkubo, and R. Yoshida, Induction of indoleamine 2,3-dioxygenase in tumor cells transplanted into allogeneic mouse: interferon-gamma is the inducer, Adv Exp Med Biol, vol.294, p.1772076, 1991.

L. Brochez, I. Chevolet, and V. Kruse, The rationale of indoleamine 2,3 dioxygenase inhibition for cancer therapy, Eur J Cancer, vol.76, 2017.

R. D. Knox, N. Luey, L. Sioson, A. Kedziora, A. Clarkson et al., Medullary colorectal carcinoma revisited: a clinical and pathological study of 102 cases, Ann Surg Oncol, vol.22, issue.9, p.25572685, 2015.

J. Mclaughlin, K. Schalper, D. Carvajal-hausdorf, V. Velcheti, H. Haack et al., Domainspecific PD-L1 protein measurement in non-small cell lung cancer (NSCLC), J Clin Oncol, vol.5, p.8064, 2014.

S. K. Lau, P. G. Chu, and L. M. Weiss, CD163: a specific marker of macrophages in paraffin-embedded tissue samples, Am J Clin Pathol, vol.122, issue.5, 2004.

N. Suraweera, A. Duval, M. Reperant, C. Vaury, D. Furlan et al., Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR, Gastroenterology, vol.123, issue.6, 2002.

A. Umar, C. R. Boland, J. P. Terdiman, S. Syngal, A. De-la-chapelle et al., Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability, J Natl Cancer Inst, vol.96, issue.4, p.14970275, 2004.

A. Jarry, C. Bossard, C. Bou-hanna, D. Masson, E. Espaze et al., Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven,IFN-gamma-mediated epithelial damage in human colon explants, J Clin Invest, vol.118, issue.3, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00277246

A. Jarry, C. Bossard, G. Sarrabayrouse, J. F. Mosnier, and C. L. Laboisse, Loss ofinterleukin-10 or transforming growth factor ? signaling in the human colon initiates a T-helper 1 response via distinct pathways, Gastroenterology, vol.141, issue.5, pp.1887-96, 2011.

, , p.21839042

J. N. Mandrekar and S. J. Mandrekar, Cha SS Cutpoint determination methods in survival analysis using SAS®, Proceedings of the 28th SAS Users Group International Conference (SUGI), 2003.