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Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond

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Abstract

Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.

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References

  1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase I study of pembrolizumab (MK-3475; Anti–PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–93.

    CAS  PubMed  Google Scholar 

  3. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of Anti-PD-L1 Antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–30.

    CAS  PubMed  Google Scholar 

  6. Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H, Bindea G, et al. Correlation between density of CD8 + T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res. 2015;75:3446–55.

    CAS  PubMed  Google Scholar 

  7. Marisa L, Svrcek M, Collura A, Becht E, Cervera P, Wanherdrick K, et al. The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors. J Natl Cancer Inst. 2018;110:68–77.

    CAS  Google Scholar 

  8. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51.

    CAS  PubMed  Google Scholar 

  9. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Overman M, Lonardi S, Wong K, Lenz H, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773–9.

    CAS  PubMed  Google Scholar 

  11. Overman M, McDermott R, Leach J, Lonardi S, Lenz H, Morse M, 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. 2017;18:1182–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20:849–61.

    CAS  PubMed  Google Scholar 

  14. Samstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Muzny DM, Bainbridge MN, Chang K, Dinh HH, Drummond JA, Fowler G, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    CAS  Google Scholar 

  16. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J Clin Oncol. 2016;34(suppl):103.

    Google Scholar 

  18. Le DT, Kavan P, Won Kim T, Burge M, Van Cutsem E, Hara H, et al. KEYNOTE-164: Pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer. J Clin Oncol. 2018;36(suppl):3514.

    Google Scholar 

  19. Diaz L, Marabelle A, Kim TW, Geva R, Van Cutsem E, Andre T, et al. Efficacy of pembrolizumab in phase 2 KEYNOTE-164 and KEYNOTE-158 studies of microsatellite instability high cancers. Ann Oncol. 2017;28:386P.

    Google Scholar 

  20. Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability–high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2019. https://doi.org/10.1200/JCO.19.02107.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Overman MJ, Lonardi S, Wong KYM, Lenz H-J, Gelsomino F, Aglietta M, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): long-term follow-up. J Clin Oncol. 2019;37(suppl):635.

    Google Scholar 

  22. Overman MJ, Bergamo F, McDermott RS, Aglietta M, Chen F, Gelsomino F, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): long-term survival according to prior line of treatment from CheckMate-142. J Clin Oncol. 2018;36(suppl):554.

    Google Scholar 

  23. Lenz H-JJ, Van Cutsem E, Limon ML, Wong KY, Hendlisz A, Aglietta M, et al. LBA18_PRDurable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann Oncol. 2018;29:mdy424.019.

  24. Segal NH, Wainberg ZA, Overman MJ, Ascierto PA, Arkenau H-T, Butler MO, et al. Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability-high (MSI-H) tumors. J Clin Oncol. 2019;37(suppl):670.

    Google Scholar 

  25. Cohen R, Hain E, Buhard O, Guilloux A, Bardier A, Kaci R, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol. 2019;5(4):551–5.

    PubMed  Google Scholar 

  26. Svrcek M, Lascols O, Cohen R, Collura A, Jonchère V, Fléjou J-F, et al. MSI/MMR-deficient tumor diagnosis: which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors. Bull Cancer (Paris). 2019;106:119–28.

    PubMed  Google Scholar 

  27. O’Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One. 2017;12:e0189848.

    PubMed  PubMed Central  Google Scholar 

  28. Cohen R, Buhard O, Cervera P, Hain E, Dumont S, Bardier A, et al. Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. Eur J Cancer. 2017;86:266–74.

    CAS  PubMed  Google Scholar 

  29. Salvador MU, Truelson MRF, Mason C, Souders B, LaDuca H, Dougall B, et al. Comprehensive paired tumor/germline testing for lynch syndrome: bringing resolution to the diagnostic process. J Clin Oncol. 2019;37:647–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kopetz S, André T, Overman MJ, Zagonel V, Lonardi S, Aglietta M, et al. Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-defıcient/microsat- ellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab plus ipilimumab in CheckMate-142. Proc Am Assoc Cancer Res. 2018;59:2603.

    Google Scholar 

  31. Sveen A, Johannessen B, Tengs T, Danielsen SA, Eilertsen IA, Lind GE, et al. Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1. Genome Med. 2017;9:46.

    PubMed  PubMed Central  Google Scholar 

  32. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188–201.

    CAS  PubMed  Google Scholar 

  34. Middha S, Yaeger R, Shia J, Stadler ZK, King S, Guercio S, et al. Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis Oncol. 2019. https://doi.org/10.1200/PO.18.00321.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Routy B, Chatelier EL, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.

    CAS  PubMed  Google Scholar 

  36. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.

    CAS  PubMed  Google Scholar 

  37. Llosa NJ, Luber B, Siegel N, Awan AH, Oke T, Zhu Q, et al. Immunopathologic stratification of colorectal cancer for checkpoint blockade immunotherapy. Cancer Immunol Res. 2019;7(10):1574–9.

    PubMed  PubMed Central  Google Scholar 

  38. Mandal R, Samstein RM, Lee K-W, Havel JJ, Wang H, Krishna C, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science. 2019;364:485–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Schrock AB, Ouyang C, Sandhu J, Sokol E, Jin D, Ross JS, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019;30:1096–103.

    CAS  PubMed  Google Scholar 

  40. Tachon G, Frouin E, Karayan-Tapon L, Auriault M-L, Godet J, Moulin V, et al. Heterogeneity of mismatch repair defect in colorectal cancer and its implications in clinical practice. Eur J Cancer. 2018;95:112–6.

    PubMed  Google Scholar 

  41. Kim ST, Cristescu R, Bass AJ, Kim K-M, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–58.

    CAS  PubMed  Google Scholar 

  42. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 2017;171(1042–1056):e10.

    Google Scholar 

  43. Gerwing M, Herrmann K, Helfen A, Schliemann C, Berdel WE, Eisenblätter M, et al. The beginning of the end for conventional RECIST—novel therapies require novel imaging approaches. Nat Rev Clin Oncol. 2019;16(7):442–58.

    CAS  PubMed  Google Scholar 

  44. Sehdev A, Cramer HM, Ibrahim AAM, Younger AE, O’Neil BH. Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature. Discov Med. 2016;21:341–7.

    PubMed  Google Scholar 

  45. Stadler ZK, Battaglin F, Middha S, Hechtman JF, Tran C, Cercek A, et al. Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels. J Clin Oncol. 2016;34:2141–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018;7:746–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ahn S-M, Ansari AA, Kim J, Kim D, Chun S-M, Kim J, et al. The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy. Oncotarget. 2016;7:68638–49.

    PubMed  PubMed Central  Google Scholar 

  48. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16:71–81.

    CAS  PubMed  Google Scholar 

  49. Bourdais R, Rousseau B, Pujals A, Boussion H, Joly C, Guillemin A, et al. Polymerase proofreading domain mutations: new opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency. Crit Rev Oncol Hematol. 2017;113:242–8.

    PubMed  Google Scholar 

  50. Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol. 2016;1:207–16.

    PubMed  Google Scholar 

  51. Guerra J, Pinto C, Pinto D, Pinheiro M, Silva R, Peixoto A, et al. POLE somatic mutations in advanced colorectal cancer. Cancer Med. 2017;6:2966–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gong J, Wang C, Lee PP, Chu P, Fakih M. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation. J Natl Compr Canc Netw. 2017;15:142–7.

    PubMed  Google Scholar 

  53. Santin AD, Bellone S, Buza N, Choi J, Schwartz PE, Schlessinger J, et al. Regression of chemotherapy-resistant polymerase ε (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res. 2016;22:5682–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bhangoo MS, Boasberg P, Mehta P, Elvin JA, Ali SM, Wu W, et al. Tumor mutational burden guides therapy in a treatment refractory POLE-mutant uterine carcinosarcoma. Oncologist. 2018;23:518–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.

    CAS  PubMed  Google Scholar 

  56. Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry S, Couture F, et al. CCTG CO.26: Updated analysis and impact of plasma-detected microsatellite stability (MSS) and tumor mutation burden (TMB) in a phase II trial of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with refractory metastatic colorectal carcinoma (rmCRC). J Clin Oncol. 2019;37(15_suppl):3512. https://doi.org/10.1200/JCO.2019.37.15_suppl.3512.

    Article  Google Scholar 

  57. Artyomenko A, Sikora M, Lefterova M, Raymond VM, Gavino D, Barbacioru C, et al. Microsatellite instability detection by targeted sequencing of cell-free DNA. Ann Oncol. 2018;29:viii400–41.

  58. Wang F, Zhao Q, Wang Y-N, Jin Y, He M-M, Liu Z-X, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.2963.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24:1441–8.

    CAS  PubMed  Google Scholar 

  60. Khagi Y, Goodman AM, Daniels GA, Patel SP, Sacco AG, Randall JM, et al. Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin Cancer Res. 2017;23:5729–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Angelova M, Charoentong P, Hackl H, Fischer ML, Snajder R, Krogsdam AM, et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 2015;16:64.

    PubMed  PubMed Central  Google Scholar 

  62. Angelova M, Mlecnik B, Vasaturo A, Bindea G, Fredriksen T, Lafontaine L, et al. Evolution of metastases in space and time under immune selection. Cell. 2018;175(751–765):e16.

    Google Scholar 

  63. 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. 2006;313:1960–4.

    CAS  PubMed  Google Scholar 

  64. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:2128–39.

    PubMed  Google Scholar 

  65. Kwak Y, Koh J, Kim D-W, Kang S-B, Kim WH, Lee HS. Immunoscore encompassing CD3 + and CD8 + T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer. Oncotarget. 2016;7:81778–90.

    PubMed  PubMed Central  Google Scholar 

  66. Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018;48:434–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Becht E, de Reyniès A, Giraldo NA, Pilati C, Buttard B, Lacroix L, et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res. 2016;22:4057–66.

    CAS  PubMed  Google Scholar 

  68. Karpinski P, Rossowska J, Sasiadek MM. Immunological landscape of consensus clusters in colorectal cancer. Oncotarget. 2017;8:105299–311.

    PubMed  PubMed Central  Google Scholar 

  69. Laurent-Puig P, Marisa L, Ayadi M, Blum Y, Balogoun R, Pilati C, et al. 60PDColon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8. Ann Oncol. 2018;29(suppl):mdy269.058.

  70. Woolston A, Khan K, Spain G, Barber LJ, Griffiths B, Gonzalez-Exposito R, et al. Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer. Cancer Cell. 2019;36(35–50):e9.

    Google Scholar 

  71. Jung B, Staudacher JJ, Beauchamp D. Transforming growth factor β superfamily signaling in development of colorectal cancer. Gastroenterology. 2017;152:36–52.

    CAS  PubMed  Google Scholar 

  72. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–43.

    CAS  PubMed  Google Scholar 

  73. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Manzoni M, Rovati B, Ronzoni M, Loupakis F, Mariucci S, Ricci V, et al. Immunological effects of bevacizumab-based treatment in metastatic colorectal cancer. Oncology. 2010;79:187–96.

    CAS  PubMed  Google Scholar 

  76. Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 2018;8:730–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Xiao Q, Wu J, Wang W-J, Chen S, Zheng Y, Yu X, et al. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med. 2018;24:262–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. 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. 2019;37:2522.

    Google Scholar 

  79. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44:343–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Holubec L, Polivka J, Safanda M, Karas M, Liska V. The role of cetuximab in the induction of anticancer immune response in colorectal cancer treatment. Anticancer Res. 2016;36:4421–6.

    CAS  PubMed  Google Scholar 

  82. Pelster MS, Amaria RN. Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials. Ther Adv Med Oncol. 2019;11:1758835919830826.

    PubMed  PubMed Central  Google Scholar 

  83. Vanpouille-Box C, Formenti SC, Demaria S. Toward precision radiotherapy for use with immune checkpoint blockers. Clin Cancer Res. 2018;24:259–65.

    CAS  PubMed  Google Scholar 

  84. Weintraub K. Take two: combining immunotherapy with epigenetic drugs to tackle cancer. Nat Med. 2016;22:8–10.

    CAS  PubMed  Google Scholar 

  85. Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11:1–25.

    Google Scholar 

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Acknowledgements

We would like to thank Michelle Lamendola-Essel for editing assistance.

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  1. Romain Cohen and Benoît Rousseau contributed equally.

Authors and Affiliations

  1. Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France

    Romain Cohen, Raphaël Colle & Thierry André

  2. Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA

    Benoît Rousseau, Joana Vidal & Luis A. Diaz Jr.

  3. Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC Instituto de Salud Carlos III, Barcelona, Spain

    Joana Vidal

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Benoît Rousseau served in a consulting/advisory role for Bayer, Roche, Novartis, Gilead, and Servier and has received travel, accommodation, and other expenses from Bayer, Servier, and Astellas. Joana Vidal has received honoraria for advisory role, speaker or travel grants from Amgen, Hoffman La-Roche, Merck-Serono, Sanofi, and Sysmex Inostics. Romain Cohen has received honoraria from Amgen, Sanofi, and Servier, and travel fees from Sanofi. Thierry André reported receiving honoraria from Roche, Genentech, Ventana, Sanofi, Bristol-Myers Squibb, MSD Oncology, Servier, and Pierre Fabre; consulting or advisory role for Roche, Amgen, Bristol-Myers Squibb, and HalioDX; speakers’ bureau for Bristol-Myers Squibb and Servier; travel, accommodation, and other expenses from Roche, Genentech, Amgen, and Bristol-Myers Squibb. Raphaël Colle and Luis A Jr Diaz declare that they have no conflicts of interest that might be relevant to the contents of this article.

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Cohen, R., Rousseau, B., Vidal, J. et al. Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond. Targ Oncol 15, 11–24 (2020). https://doi.org/10.1007/s11523-019-00690-0

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