, Papers of special note have been highlighted as either of interest (?) or of considerable interest (??) to readers

, GLOBOCAN. International agency for research on cancer, 2018.

, Cancer facts & figures, 2019.

R. L. Siegel, K. D. Miller, and S. A. Fedewa, Colorectal cancer statistics, CA Cancer J Clin, vol.67, issue.3, pp.177-193, 2017.

J. Y. Douillard, Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer, Oncology, vol.14, issue.12, pp.51-55, 2000.

A. Falcone, S. Ricci, and I. Brunetti, Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the GruppoOncologicoNordOvest, J Clin Oncol, vol.25, issue.13, pp.1670-1676, 2007.

A. Degramont, A. Figer, and M. Seymour, Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer, J Clin Oncol, vol.18, issue.16, pp.2938-2947, 2000.

L. B. Saltz, S. Clarke, and E. Díaz-rubio, Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study, J Clin Oncol, vol.26, issue.12, pp.2013-2019, 2008.

E. Van-cutsem, C. Köhne, and I. Láng, Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status, J Clin Oncol, vol.29, issue.15, pp.2011-2019, 2011.

A. Grothey, E. V. Cutsem, and A. Sobrero, Regorafenibmonotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial, Lancet, vol.381, issue.9863, pp.303-312, 2013.

T. Yoshino, N. Mizunuma, and K. Yamazaki, TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial, Lancet Oncol, vol.13, issue.10, pp.993-1001, 2012.

F. Gelsomino, M. Barbolini, and A. Spallanzani, The evolving role of microsatellite instability in colorectal cancer: a review, Cancer Treat Rev, vol.51, pp.19-26, 2016.

Y. M. Hendriks, A. E. De-jong, and H. Morreau, Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians, CA Cancer J Clin, vol.56, issue.4, pp.213-225, 2006.

H. Hampel, W. L. Frankel, and E. Martin, Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer), N Engl J Med, vol.352, issue.18, pp.1851-1860, 2005.

H. T. Lynch, T. C. Smyrk, and P. Watson, Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review, Gastroenterology, vol.104, issue.5, pp.1535-1549, 1993.

A. Malesci, L. Laghi, and P. Bianchi, Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer, Clin Cancer Res, vol.13, issue.13, pp.3831-3839, 2007.

A. D. Roth, M. Delorenzi, and S. Tejpar, Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer, J Natl Cancer Inst, vol.104, issue.21, pp.1635-1646, 2012.

S. Popat, R. Hubner, and R. S. Houlston, Systematic review of microsatellite instability and colorectal cancer prognosis, JClinOncol, vol.23, issue.3, pp.609-618, 2005.

J. K. Greenson, J. D. Bonner, and O. Ben-yzhak, Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability, Am J Surg Pathol, vol.27, pp.563-570, 2003.

B. Mlecnik, G. Bindea, and H. K. Angell, Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability, Immunity, vol.44, issue.3, pp.698-711, 2016.
URL : https://hal.archives-ouvertes.fr/hal-02379906

J. Guinney, R. Dienstmann, and X. Wang, The consensus molecular subtypes of colorectal cancer, Nat Med, vol.21, issue.11, pp.1350-1356, 2015.

H. Sun, X. Zhou, and Y. Xue, Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma, World J Gastroenterol, vol.18, issue.25, pp.3303-3309, 2012.

M. J. Overman, R. Mcdermott, and J. L. Leach, 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.1182-1191, 2017.

, ? Results of CheckMate 142 evalating the efficacy of anti-PD1 in MSI CRC

M. A. Morse, M. J. Overman, and L. Hartman, Safety of nivolumab plus low-dose ipilimumab in previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer, Oncologist, vol.24, pp.1453-1461, 2019.

J. Eugène, N. Jouand, and K. Ducoin, The inhibitory receptor CD94/ NKG2A on CD8+ tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE/?2m overexpression, Mod Pathol, 2019.

N. A. Rizvi, M. D. Hellmann, and A. Snyder, Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, vol.348, issue.6230, pp.124-128, 2015.

T. N. Schumacher and R. D. Schreiber, Neoantigens in cancer immunotherapy, Science, vol.348, issue.6230, pp.69-74, 2015.

R. M. Samstein, C. Lee, and A. N. Shoushtari, Tumor mutational load predicts survival after immunotherapy across multiple cancer types, Nat Genet, vol.51, issue.2, pp.202-206, 2019.

, Evaluation of TMB as a predictive factor of response to immunotherapy

E. Domingo, L. Freeman-mills, and E. Rayner, Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study, Lancet Gastroenterol Hepatol, vol.1, issue.3, pp.207-216, 2016.

E. Rayner, I. C. Van-gool, and C. Palles, A panoply of errors: polymerase proofreading domain mutations in cancer, Nat Rev Cancer, vol.16, issue.2, pp.71-81, 2016.

D. A. Fabrizio, T. J. George, . Jr, and R. F. Dunne, Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition, J Gastrointest Oncol, vol.9, issue.4, pp.610-617, 2018.

D. Muzny, M. Bainbridge, and C. K. , Cancer genome atlas network. Comprehensive molecular characterization of human colon and rectal cancer, Nature, vol.487, issue.7407, pp.330-337, 2012.

R. Bourdais, B. Rousseau, and A. Pujals, Polymerase proofreading domain mutations: new opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency, Crit Rev OncolHematol, vol.113, pp.242-248, 2017.

J. Gong, C. Wang, . Lee, and . Pp, Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation, J Natl Compr Cancer Network, vol.15, issue.2, pp.142-147, 2017.

D. Tauriello, S. Palomo-ponce, and D. Stork, TGF? drives immune evasion in genetically reconstituted colon cancer metastasis, Nature, vol.554, issue.7693, pp.538-543, 2018.

J. Roelands, P. Kuppen, and L. Vermeulen, Immunogenomic classification of colorectal cancer and therapeutic implications, Int J Mol Sci, vol.18, p.10, 2017.

E. Becht, A. De-reyniès, and N. A. Giraldo, Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy, Clin Cancer Res, vol.22, issue.16, pp.4057-4066, 2016.

D. Ciardiello, P. P. Vitiello, and C. Cardone, Immunotherapy of colorectal cancer: challenges for therapeutic efficacy, Cancer Treat Rev, vol.76, pp.22-32, 2019.

A. Patnaik, S. P. Kang, and D. Rasco, Phase I Study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors, Clin Cancer Res, vol.21, pp.4286-4293, 2015.

M. Wang, L. Guo, and F. Xia, Safety and efficacy profile of Pembrolizumab in solid cancer: pooled reanalysis based on randomized controlled trials, Drug Des Devel Ther, vol.11, pp.2851-2860, 2017.

J. Haanen, F. Carbonnel, and C. Robert, Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up, Ann Oncol, vol.28, issue.suppl4, pp.119-142, 2017.

B. H. O'neil, J. M. Wallmark, and D. Lorente, Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma, PLoS One, vol.12, issue.12, p.189848, 2017.

?. , Results of KEYNOTE-028, phase I trial showing efficacy of pembrolizumab in PDL1 tumors including CRC

D. T. Le, J. N. Uram, and H. Wang, PD-1 blockade in tumors with mismatch-repair deficiency, NEngl J Med, vol.372, issue.26, pp.2509-2520, 2015.

?. Results, KEYNOTE-016 showing effect of Pembrolizumab in MSI-H CRC led to FDA approval

D. T. Le, T. Yoshino, and D. Jäger, KEYNOTE-164: phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma, J Clin Oncol, vol.34, pp.787-787, 2016.

H. C. Chung, R. W. Delord, and J. P. , Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study, J Clin Oncol, vol.37, issue.17, pp.1470-1478, 2019.

D. T. Le, P. Kavan, and T. W. Kim, KEYNOTE-164: pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer, J Clin Oncol, vol.36, p.3514, 2018.

, ? Results of KEYNOTE-164 phase II study focusing on pembrolizumab in MSI-H colorectal cancer

L. Marcus, S. J. Lemery, and P. Keegan, FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors, Clin Cancer Res, vol.25, issue.13, pp.3753-3758, 2019.

L. A. Diaz, D. T. Le, and T. Yoshino, KEYNOTE-177: phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC), J Clin Oncol, vol.36, pp.877-877, 2018.

, Abstract from the KEYNOTE 177: phase III study comparing chemotherapy and pembrolizumab for the treatment of MSI-H colorectal carcinoma

L. A. Emens and G. Middleton, The interplay of immunotherapy and chemotherapy: harnessing potential synergies, Cancer Immunol Res, vol.3, issue.5, pp.436-443, 2015.

S. Shahda, A. M. Noonan, and T. S. Bekaii-saab, A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer, J Clin Oncol, vol.35, p.3541, 2017.

M. Vanneman and G. Dranoff, Combining immunotherapy and targeted therapies in cancer treatment, Nat Rev Cancer, vol.12, issue.4, pp.237-251, 2012.

M. Dechant, W. Weisner, and S. Berger, Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies, Cancer Res, vol.68, issue.13, pp.4998-5003, 2008.

T. Omaya, S. Ran, and T. Ishida, ascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells, J Immunol, vol.160, issue.3, pp.1224-1232, 1998.

T. Voron, O. Colussi, and E. Marcheteau, VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors, J Exp Med, vol.212, issue.2, pp.139-148, 2009.

J. E. Ohm, D. I. Gabrilovich, and G. D. Sempowski, VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression, Blood, vol.101, issue.12, pp.4878-4886, 2003.

J. C. Bendell, J. D. Powderly, and C. H. Lieu, Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC), J Clin Oncol, vol.33, p.704, 2015.

L. Abou-elkacem, S. Arns, and G. Brix, Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model, Mol Cancer Ther, vol.12, issue.7, pp.1322-1331, 2013.

S. Fukuoka, H. Hara, and N. Takahashi, Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): an open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603), J Clin Oncol, vol.37, p.2522, 2019.

E. Shinozaki, A. Kawazoe, and Y. Kuboki, Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP study): EPOC1503, J Clin Oncol, vol.36, issue.15_suppl, p.3530, 2018.

N. S. Azad, K. Shirai, and A. J. Mcree, ENCORE 601: a phase 2 study of entinostat in combination with pembrolizumab in patients with microsatellite stable metastatic colorectal cancer, J Clin Oncol, vol.36, issue.15_suppl, p.3557, 2018.

E. Chajon, J. Castelli, and H. Marsiglia, The synergistic effect of radiotherapy and immunotherapy: a promising but notsimple partnership, Crit Rev Oncol Hematol, vol.111, pp.124-132, 2017.

J. J. Lee, W. Sun, and N. Bahary, Phase 2 study of pembrolizumab in combination with azacitidine in subjects with metastatic colorectal cancer, J Clin Oncol, vol.35, issue.15_suppl, p.3054, 2017.

M. Yarchoan, A. K. Ferguson, and J. N. Durham, A phase II study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair-proficient (MMR-p) advanced colorectal cancer, J Clin Oncol, vol.37, p.563, 2019.

M. Chalabi, L. F. Fanchi, and J. G. Van-den-berg, LBA37_PR neoadjuvantipilimumab plus nivolumab in early stage colon cancer, Ann Oncol, vol.29, issue.suppl_8, 2018.