The colorectal cancer immune microenvironment and approach to immunotherapies

Future OncologyVol. 13, No. 18 ReviewThe colorectal cancer immune microenvironment and approach to immunotherapiesMinoru Koi & John M CarethersMinoru Koi Division of Gastroenterology, Department of Internal Medicine & Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA & John M Carethers*Author for correspondence: Tel.: +1 734 615 1717; Fax: +1 734 936 7024; E-mail Address: jcarethe@umich.edu Division of Gastroenterology, Department of Internal Medicine & Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USAPublished Online:22 Aug 2017https://doi.org/10.2217/fon-2017-0145AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: colorectal cancercolorectal cancer molecular subtypeDNA mismatch repairEMASTimmune checkpoint inhibitorimmunotherapyimmunotypingmicrosatellite instabilitypatient outcometumor microenvironmentPapers of special note have been highlighted as: •• of considerable interestReferences1 Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), E359–E386 (2015).Crossref, Medline, CAS, Google Scholar2 Siegel RL, Miller KD, Fedewa SA et al. Colorectal cancer statistics, 2017. CA Cancer J. Clin. 67(3), 177–193 (2017).Crossref, Medline, Google Scholar3 Pages F, Berger A, Camus M et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353(25), 2654–2666 (2005).Crossref, Medline, CAS, Google Scholar4 Galon J, Costes A, Sanches-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795), 1960–1964 (2006).Crossref, Medline, CAS, Google Scholar5 Camus M, Tosolini M, Mlecnik B et al. Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res. 69(6), 2685–2693 (2009).Crossref, Medline, CAS, Google Scholar6 Pages F, Kirilovsky A, Melecnik B et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27(35), 5944–5951 (2009).Crossref, Medline, CAS, Google Scholar7 Tosolini M, Kirilovsky A, Mlecnik B 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. 71(4), 1263–1271 (2011).Crossref, Medline, CAS, Google Scholar8 Mlecnik B, Bindea G, Kirilovsky A et al. The tumor microenvironment and immunoscore are critical determinants of dissemination to distant metastasis. Sci. Transl. Med. 8(327), 327ra26 (2016). •• Describes the use of the immunoscore, and how it may be better than stage or microsatellite instable classification.Crossref, Medline, Google Scholar9 Becht E, de Reyniès A, Giraldo NA et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22(16), 4057–4066 (2016).Crossref, Medline, CAS, Google Scholar10 Galon J, Pages F, Marincola FM et al. Cancer classification using the immunoscore: a worldwide task force. J. Transl. Med. 10, 205 (2012).Crossref, Medline, Google Scholar11 Eggermont AMM, Chiarion-Sileni V, Grob J-J et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375(19), 1845–1855 (2016).Crossref, Medline, CAS, Google Scholar12 Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012). •• Initial clinical trial data and demonstration of the effectiveness of PD-1 blockade for cancer.Crossref, Medline, CAS, Google Scholar13 Brahmer JR, Tykodi SS, Chow LQM et al. Safety and activity of anti-PDL1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–2465 (2012).Crossref, Medline, CAS, Google Scholar14 Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015). •• Initial description of use of PD-1 inhibitor and specific response in patients with microsatellite instability colorectal cancers (CRCs).Crossref, Medline, CAS, Google Scholar15 MacCarty WC. Factors which influences longevity in cancer. Ann. Surg. 76, 9–12 (1922).Medline, CAS, Google Scholar16 Underwood JCE. Lymphoreticular infiltration in human tumors: prognostic and biological implications: a review. Br. J. Cancer 30, 538–548 (1974).Crossref, Medline, CAS, Google Scholar17 Murray D, Hreno A, Dutton J, Hampson LG. Prognosis in colon cancer A pathologic reassessment. Arch. Surg. 110, 908–913 (1975).Crossref, Medline, CAS, Google Scholar18 Watt AG, House AK. Colonic carcinoma A quantitative assessment of lymphocyte infiltration at periphery of colonic tumors related to prognosis. Cancer 41, 279–282 (1978).Crossref, Medline, CAS, Google Scholar19 Engel P, Boumsell L, Balderas R et al. CD nomenclature 2015: human leukocyte differentiation antigen workshops as a driving force in immunology. J. Immunol. 195, 4555–4563 (2015).Crossref, Medline, CAS, Google Scholar20 Muul LM, Spiess PJ, Director EP, Rosenberg SA. Identification of specific cytolytic immune response against autologous tumor in humans bearing malignant melanoma. J. Immunol. 138, 989–995 (1987).Medline, CAS, Google Scholar21 Gallagher P, Vose BM, Moore M, Schofield PF. Role of autologous lymphocyte cytotoxicity in colonic neoplasia. Gut 23, 31–35 (1982).Crossref, Medline, CAS, Google Scholar22 Ebert EC, Brolin RE, Roberts AI. Characterization of activated lymphocytes in colon cancer. Clin. Immunol. Immunopathol. 50(1 Pt 1), 72–81 (1989).Crossref, Medline, CAS, Google Scholar23 Vose BM, Moor M. Suppressor cell activity of lymphocytes infiltrating human lung and breast tumors. Int. J. Cancer 24, 579–585 (1979).Crossref, Medline, CAS, Google Scholar24 Holmes EC. Immunology of tumor infiltrating lymphocytes. Ann. Surg. 201, 158–163 (1985).Crossref, Medline, CAS, Google Scholar25 Jass JR. Lymphocytic infiltration and survival in rectal cancer. J. Clin. Pathol. 39, 585–589 (1986).Crossref, Medline, CAS, Google Scholar26 Ogino S, Nosho K, Irahara N et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin. Cancer Res. 15(20), 6412–6420 (2009).Crossref, Medline, CAS, Google Scholar27 Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393(6684), 480–483 (1998).Crossref, Medline, CAS, Google Scholar28 Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol. 2(6), 401–409 (2002).Crossref, Medline, CAS, Google Scholar29 Naito Y, Saito K, Shiiba K et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58, 3491–3494 (1998).Medline, CAS, Google Scholar30 Mlecnik B, Tosolini M, Charoentong P et al. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138(4), 1429–1440 (2010).Crossref, Medline, CAS, Google Scholar31 Rozek LS, Schmit SL, Greenson JK et al. Tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and survival from colorectal cancer. J. Natl Cancer Inst. 108(8), djw027 (2016).Crossref, Google Scholar32 Mlecnik B, Tosolini M, Kirilovsky A et al. Histopathologic based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 29, 610–618 (2011).Crossref, Medline, Google Scholar33 Bindea G, Mlecnik B, Tosolini M et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39(4), 782–795 (2013).Crossref, Medline, CAS, Google Scholar34 Angelova M, Charoentong P, Hackl H et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).Crossref, Medline, Google Scholar35 Bronte Vincenzo, Brandau Sven, Chen Shu-Hsia et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).Crossref, Medline, CAS, Google Scholar36 OuYang LY, Wu XJ, Ye SB et al. Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer. J. Transl. Med. 13, 47 (2015).Crossref, Medline, Google Scholar37 Dalton DK, Noelle RJ. The roles of mast cells in anticancer immunity. Cancer Immunol. Immunother. 61(9), 1511–1520 (2012).Crossref, Medline, CAS, Google Scholar38 Yodavudh S, Tangjitgamol S, Puangsa-art S. Prognostic significance of microvessel density and mast cell density for the survival of Thai patients with primary colorectal cancer. J. Med. Assoc. Thai. 91, 723–732 (2008).Medline, Google Scholar39 Amicarella F, Muraro MG, Hirt C et al. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut 66, 692–704 (2015).Crossref, Medline, Google Scholar40 De Simone M, Arrigoni A, Rossetti G et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45(5), 1135–1147 (2016).Crossref, Medline, CAS, Google Scholar41 Torres S, Bartolomé RA, Mendes M et al. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin. Cancer Res. 19(21), 6006–6019 (2013).Crossref, Medline, CAS, Google Scholar42 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).Crossref, Medline, Google Scholar43 Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology 149, 1177–1190 (2015).Crossref, Medline, CAS, Google Scholar44 Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135, 1079–1099 (2008).Crossref, Medline, CAS, Google Scholar45 Carethers JM, Koi M, Tseng-Rogenski S. EMAST is a form of microsatellite instability that is initiated by inflammation and modulates colorectal cancer progression. Genes 6, 185–205 (2015).Crossref, Medline, CAS, Google Scholar46 Koi M, Umar A, Chauhan DP et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 54, 4308–4314 (1994).Medline, CAS, Google Scholar47 Carethers JM, Hawn MT, Chauhan DP et al. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. J. Clin. Invest. 98, 199–206 (1996).Crossref, Medline, CAS, Google Scholar48 Carethers JM, Stoffel EM. Lynch syndrome and Lynch syndrome mimics: the growing complex landscape of hereditary colon cancer. World J. Gastroenterol. 21, 9253–9261 (2015).Crossref, Medline, CAS, Google Scholar49 Carethers JM. Microsatellite instability pathway and EMAST in colorectal cancer. Curr. Colorectal Cancer Rep. 13(1), 73–80 (2017). •• Overview of microsatellite instability in CRCs and multiple clinic pathological correlates including immune response.Crossref, Medline, Google Scholar50 Schwitalle Y, Kloor M, Eiermann S et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134, 988–997 (2008).Crossref, Medline, CAS, Google Scholar51 Tseng-Rogenski SS, Chung H, Wilk MB, Zhang S, Iwaizumi M, Carethers JM. Oxidative stress induces nuclear-to-cytosol shift of hMSH3, a potential mechanism for EMAST in colorectal cancer cells. PLoS ONE 7(11), e50616 (2012).Crossref, Medline, CAS, Google Scholar52 Tseng-Rogenski SS, Hamaya Y, Choi DY, Carethers JM. Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology 148(3), 579–589 (2015). •• Demonstrates how inflammation can directly affect DNA repair in colon cancers.Crossref, Medline, CAS, Google Scholar53 Campregher C, Schmid G, Ferk F et al. MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells. PLoS ONE 7(11), e50541 (2012).Crossref, Medline, CAS, Google Scholar54 Boland CR, Thibodeau SN, Hamilton SR et al. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58, 5248–5257 (1988).Google Scholar55 Hamaya Y, Guarinos C, Tseng-Rogenski SS et al. Efficacy of 5-fluorouracil adjuvant therapy for patients with EMAST-positive stage II/III colorectal cancers. PLoS ONE 10, e0127591 (2015). •• Demonstrates the fidelity of DNA mismatch repair to recognize 5-fluorouracil for patient survival.Crossref, Medline, Google Scholar56 Haugen AC, Goel A, Yamada K et al. Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res. 68(20), 8465–8472 (2008).Crossref, Medline, CAS, Google Scholar57 Yamada K, Kanazawa S, Koike J et al. Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan. Oncol. Rep. 23(2), 551–561 (2010).Medline, CAS, Google Scholar58 Lee SY, Chung H, Devaraj B et al. Microsatellite alterations at selected tetranucleotide repeats are associated with morphologies of colorectal neoplasias. Gastroenterology 139(5), 1519–1525 (2010).Crossref, Medline, CAS, Google Scholar59 Lee SY, Miyai K, Han HS et al. Microsatellite instability, EMAST, and morphology associations with T cell infiltration in colorectal neoplasia. Dig. Dis. Sci. 57(1), 72–78 (2012).Crossref, Medline, CAS, Google Scholar60 Garcia M, Choi C, Kim HR et al. Association between recurrent metastasis from stage II and III primary colorectal tumors and moderate microsatellite instability. Gastroenterology 143(1), 48–50 (2012).Crossref, Medline, CAS, Google Scholar61 Devaraj B, Lee A, Cabrera BL et al. Relationship of EMAST and microsatellite instability among patients with rectal cancer. J. Gastrointest. Surg. 14, 1521–1528 (2010).Crossref, Medline, Google Scholar62 Koi M, Garcia M, Choi C et al. Microsatellite alterations with allelic loss on 9p24.2 signify less aggressive colorectal cancer metastasis. Gastroenterology 150, 944–955 (2016). •• Demonstrates modulating genetic factors that can alter prognosis for patients with inflammatory (elevated microsatellite alterations at selected tetranucleotide repeats) CRCs.Crossref, Medline, CAS, Google Scholar63 Guinney J, Dienstmann R, Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21(11), 1350–1356 (2015).Crossref, Medline, CAS, Google Scholar64 Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23(3), 609–618 (2005).Crossref, Medline, CAS, Google Scholar65 Mlecnik B, Bindea G, Angell HK et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44(3), 698–711 (2016).Crossref, Medline, CAS, Google Scholar66 Bicknell DC, Rowan A, Bodmer WF. Beta 2-microglobulin gene mutations: a study of established colorectal cell lines and fresh tumors. Proc. Natl Acad. Sci. USA 91(11), 4751–4755 (1994).Crossref, Medline, CAS, Google Scholar67 Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int. J. Cancer 127(5), 1001–1010 (2010).Crossref, Medline, CAS, Google Scholar68 Kloor M, Becker C, Benner A et al. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res. 65, 6418–6424 (2005).Crossref, Medline, CAS, Google Scholar69 Giannakis M, Mu XJ, Shukla SA et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15(4), 857–865 (2016).Crossref, Medline, CAS, Google Scholar70 Brennan CA, Garrett WS. Gut microbiota, inflammation, and colorectal cancer. Annu. Rev. Microbiol. 70, 395–411 (2016).Crossref, Medline, CAS, Google Scholar71 Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nature Rev. Cancer 17, 271–286 (2017).Crossref, Medline, CAS, Google Scholar72 Tahara T, Yamamoto E, Suzuki H et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res. 74(5), 1311–1318 (2014).Crossref, Medline, CAS, Google Scholar73 Nosho K, Sukawa Y, Adachi Y et al. Association of Fusobacteriumnucleatum with immunity and molecular alterations in colorectal cancer. World J. Gastroenterol. 22(2), 557–566 (2016). Crossref, Medline, CAS, Google Scholar74 Mima K, Nishihara R, Qian ZR et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65, 1973–1980 (2016).Crossref, Medline, CAS, Google Scholar75 Dejea CM, Wick EC, Hechenbleikner EM et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl Acad. Sci. USA 111(51), 18321–18326 (2014).Crossref, Medline, CAS, Google Scholar76 Mima K, Sukawa Y, Nishihara R et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 1(5), 653–661 (2015).Crossref, Medline, Google Scholar77 Kaplan CW, Ma X, Paranjpe A et al. Fusobacterium nucleatum outer membrane proteins Fap2 and RadD induce cell death in human lymphocytes. Infect. Immun. 78(11), 4773–4778 (2010).Crossref, Medline, CAS, Google Scholar78 Kostic AD, Chun E, Robertson L et al. Fusobacteriumnucleatum potentiates intestinal tumorigenesis and modulates the tumor-immunemicroenvironment. Cell Host Microbe 14, 207–215 (2013).Crossref, Medline, CAS, Google Scholar79 Gur C, Ibrahim Y, Isaacson B et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355 (2015).Crossref, Medline, CAS, Google Scholar80 Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR). Cancer Biol. Ther. 8(23), 13–22 (2009).Crossref, Medline, Google Scholar81 Calon A, Lonardo E, Berenguer-Llergo A et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat. Genet. 47(4), 320–309 (2015). •• Describes consensus molecular subtypes of colon cancer, including the poor prognosis associated with cancer-associated fibroblast molecular signature.Crossref, Medline, CAS, Google Scholar82 Giraldo NA, Becht E, Pagès F et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin. Cancer Res. 21(13), 3031–3040 (2015).Crossref, Medline, CAS, Google Scholar83 Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499(7456), 43–49 (2013).Crossref, Medline, Google Scholar84 Kitajima T, Koi M, Gutierrez L et al. Loss of heterozygosity (LOH) at the hypoxia inducible factor 3A (HIF3A) locus and loss of protein expression is acquired in colorectal cancer (CRC) metastasis. Gastroenterology 150(4), S366 (2016).Crossref, Google Scholar85 Gradin K, Poellinger L, Yamamoto M. Regulation of hypoxia-inducible gene expression after HIF activation. Exp. Cell. Res. 356, 182–186 (2017).Crossref, Medline, Google Scholar86 Chia WK, Ali R, Toh HC. Aspirin as adjuvant therapy for colorectal cancer reinterpreting paradigms. Nat. Rev. Clin. Oncol. 9, 561–570 (2012).Crossref, Medline, CAS, Google Scholar87 Frouws MA, van Herk-Sukel MPP, Maas HA et al. The mortality reducing effect of aspirin in colorectal cancer patients: interpreting the evidence. Cancer Treat. Rev. 55, 120–127 (2017).Crossref, Medline, CAS, Google Scholar88 Hamada T, Cao Y, Qian ZR et al. Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status. J. Clin. Oncol. doi:10.1200/JCO.2016.70.7547 (2017) (Epub ahead of print).Crossref, Medline, Google Scholar89 Gray RT, Cantwell MM, Coleman HG et al. Evaluation of PTGS2 expression, PIK3CA mutation, aspirin use and colon cancer survival in a population-based cohort study. Clin. Transl. Gastroenterol. 8(4), e91 (2017).Crossref, Medline, Google Scholar90 Kwon ED, Foster BA, Hurwitz AA et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc. Natl Acad. Sci. USA 96(26), 15074–15079 (1999).Crossref, Medline, CAS, Google Scholar91 Vermorken JB, Claessen AM, van Tinteren H et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 353, 345–350 (1999).Crossref, Medline, CAS, Google Scholar92 Uyl-de Groot CA, Vermorken JB, Hanna MG et al. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine 23, 2379–2387 (2005).Crossref, Medline, CAS, Google Scholar93 de Weger VA, Turksma AW, Voorham QJ et al. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin. Cancer Res. 18(3), 882–889 (2012).Crossref, Medline, CAS, Google Scholar94 Zhen YH, Liu XH, Yang Y et al. Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer. Cancer Immunol. Immunother. 64(9), 1083–1093 (2015).Crossref, Medline, CAS, Google Scholar95 Mennonna D, Maccalli C, Romano MC et al. T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes. Gut 66(3), 454–463 (2017).Crossref, Medline, CAS, Google Scholar96 Seow HF, Yip WK, Fifis T. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era. Onco. Targets Ther. 9, 1899–1920 (2016).Crossref, Medline, CAS, Google Scholar97 Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369(2), 122–133 (2013).Crossref, Medline, CAS, Google Scholar98 Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010).Crossref, Medline, CAS, Google Scholar99 Chung KY, Gore I, Fong L et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 28(21), 3485–3490 (2010).Crossref, Medline, CAS, Google Scholar100 Brahmer JR, Drake CG, Wollner I 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. 28(19), 3167–3175 (2010)Crossref, Medline, CAS, Google Scholar101 Overman MJ, Kopetz S, McDermott RS 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(Suppl.), Abstract 3501 (2016).Google Scholar102 Bendell JC, Powderly JD, Lieu CH et al. 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. 33 (Suppl.) Abstract 704 (2015).Crossref, Google Scholar103 Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39(1), 74–88 (2013).Crossref, Medline, CAS, Google Scholar104 Tesniere A, Schlemmer F, Boige V et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29(4), 482–491 (2010).Crossref, Medline, CAS, Google Scholar105 Vincent J, Mignot G, Chalmin F et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).Crossref, Medline, CAS, Google Scholar106 Kakarla S, Song XT, Gottschalk S. Cancer-associated fibroblasts as targets for immunotherapy. Immunotherapy 4(11), 1129–1138 (2012).Link, CAS, Google Scholar107 Cheng JD, Valianou M, Canutescu AA et al. Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol. Cancer Ther. 4(3), 351–360 (2005).Crossref, Medline, CAS, Google Scholar108 Scott AM, Wiseman G, Welt S et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9(5), 1639–1647 (2003).Medline, CAS, Google Scholar109 Chen M, Xiang R, Wen Y et al. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Sci. Rep. 5, 14421 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByImmune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer24 February 2023 | Cancers, Vol. 15, No. 5Construction of a TTN Mutation-Based Prognostic Model for Evaluating Immune Microenvironment, Cancer Stemness, and Outcomes of Colorectal Cancer PatientsStem Cells International, Vol. 2023Classification of colorectal cancer into clinically relevant subtypes based on genes and mesenchymal cells22 October 2022 | Clinical and Translational Oncology, Vol. 25, No. 2Dynamic increase of M2 macrophages is associated with disease progression of colorectal cancers following cetuximab-based treatment31 January 2022 | Scientific Reports, Vol. 12, No. 1Novel six-gene prognostic signature based on colon adenocarcinoma immune-related genes11 October 2022 | BMC Bioinformatics, Vol. 23, No. 1System analysis based on the ER stress-related genes identifies WFS1 as a novel therapy target for colon cancer28 November 2022 | Aging, Vol. 1Genetics of Colorectal Cancer Racial Disparities5 October 2022Metabolic Pathways Regulating Colorectal Cancer: A Potential Therapeutic ApproachCurrent Pharmaceutical Design, Vol. 28, No. 36Colorectal Cancer and Purinergic Signalling: An Overview6 October 2022 | Cancers, Vol. 14, No. 19Identification of tumor microenvironment-related signature for predicting prognosis and immunotherapy response in patients with bladder cancer6 September 2022 | Frontiers in Genetics, Vol. 13Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum16 August 2022 | Cancers, Vol. 14, No. 16Commencing colorectal cancer screening at age 45 years in U.S. racial groups22 July 2022 | Frontiers in Oncology, Vol. 12Lactate Metabolism-Associated lncRNA Pairs: A Prognostic Signature to Reveal the Immunological Landscape and Mediate Therapeutic Response in Patients With Colon Adenocarcinoma11 July 2022 | Frontiers in Immunology, Vol. 13Polo‑like kinase 4 is associated with advanced TNM stages and reduced survival and its inhibition improves chemosensitivity in colorectal cancer20 June 2022 | Oncology Letters, Vol. 24, No. 2Identification of Hypoxia-Related Subtypes, Establishment of Prognostic Models, and Characteristics of Tumor Microenvironment Infiltration in Colon Cancer17 June 2022 | Frontiers in Genetics, Vol. 13Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer—Current Treatment Options and Future Perspectives15 June 2022 | International Journal of Molecular Sciences, Vol. 23, No. 12Evaluation of Galanin Expression in Colorectal Cancer: An Immunohistochemical and Transcriptomic Study30 May 2022 | Frontiers in Oncology, Vol. 12Comprehensive Analysis of Colorectal Cancer Immunity and Identification of Immune-Related Prognostic TargetsDisease Markers, Vol. 2022Potential Prognostic Value of a Seven m6A-Related LncRNAs Signature and the Correlative Immune Infiltration in Colon Adenocarcinoma22 December 2021 | Frontiers in Genetics, Vol. 12SEMA6B Overexpression Predicts Poor Prognosis and Correlates With the Tumor Immunosuppressive Microenvironment in Colorectal Cancer6 December 2021 | Frontiers in Molecular Biosciences, Vol. 8Identification of a tumor microenvironment-related seven-gene signature for predicting prognosis in bladder cancer10 June 2021 | BMC Cancer, Vol. 21, No. 1An immune-related model based on INHBA, JAG2 and CCL19 to predict the prognoses of colon cancer patients8 June 2021 | Cancer Cell International, Vol. 21, No. 1Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects24 August 2021 | Biomedicines, Vol. 9, No. 9Immune cell infiltration-associated signature in colon cancer and its prognostic implications4 August 2021 | Aging, Vol. 13, No. 15Colorectal Cancer, Liver Metastases and Biotherapies26 July 2021 | Biomedicines, Vol. 9, No. 8N6-Methylandenosine-Related lncRNA Signature Is a Novel Biomarkers of Prognosis and Immune Response in Colon Adenocarcinoma Patients15 July 2021 | Frontiers in Cell and Developmental Biology, Vol. 9CD163+ macrophages suppress T cell response by producing TGF-β in pediatric colorectal polypsInternational Immunopharmacology, Vol. 96A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers3 June 2021 | Molecules, Vol. 26, No. 11T‐cell immunoglobulin and ITIM domain, as a potential immune checkpoint target for immunotherapy of colorectal cancer30 March 2021 | IUBMB Life, Vol. 73, No. 5Colorectal Cancer and Immunity: From the Wet Lab to Individuals4 April 2021 | Cancers, Vol. 13, No. 7Prognostic Signatures Based on Thirteen Immune-Related Genes in Colorectal Cancer19 February 2021 | Frontiers in Oncology, Vol. 10The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia4 February 2021 | International Journal of Molecular Sciences, Vol. 22, No. 4Molecular correlates of immune cytolytic subgroups in colorectal cancer by integrated genomics analysis2 March 2021 | NAR Cancer, Vol. 3, No. 1Rapid screening for individualized chemotherapy optimization of colorectal cancer: A novel conditional reprogramming technology-based functional diagnostic assay.Translational Oncology, Vol. 14, No. 1Aloperine Inhibits Proliferation and Promotes Apoptosis in Colorectal Cancer Cells by Regulating the circNSUN2/miR-296-5p/STAT3 Pathway1 February 2021 | Drug Design, Development and Therapy, Vol. Volume 15Actinidia eriantha Polysaccharide and PD1-Antibody Combination Therapy Enhances Antitumor Efficacy in Colorectal Cancer–Xenograft Mice1 February 2021 | OncoTargets and Therapy, Vol. Volume 14Racial and ethnic disparities in colorectal cancer incidence and mortalityPD-1 blockade as a future treatment for colorectal cancer with microsatellite instability8 March 2021 | Journal of Coloproctology, Vol. 40, No. 04Prediction and identification of immune genes related to the prognosis of patients with colon adenocarcinoma and its mechanisms29 June 2020 | World Journal of Surgical Oncology, Vol. 18, No. 1A novel prognostic signature of immune‐related genes for patients with colorectal cancer21 June 2020 | Journal of Cellular and Molecular Medicine, Vol. 24, No. 15High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer8 May 2020 | International Journal of Oncology, Vol. 57, No. 1Carcinoma and Sarcoma Microenvironment at a Glance: Where We Are3 March 2020 | Frontiers in Oncology, Vol. 10Causes of Socioeconomic Disparities in Colorectal Cancer and Intervention Framework and StrategiesGastroenterology, Vol. 158, No. 2 Emerging Role of Immunotherapy for Colorectal Cancer with Liver Metastasis 1 November 2020 | OncoTargets and Therapy, Vol. Volume 13Mining the potential prognostic value of synaptosomal-associated protein 25 (SNAP25) in colon cancer based on stromal-immune score20 October 2020 | PeerJ, Vol. 8Clinical significance of MLH1 / MSH2 for stage II/III sporadic colorectal cancerWorld Journal of Gastrointestinal Oncology, Vol. 11, No. 11Exosomal miRNA: Small Molecules, Big Impact in Colorectal CancerJournal of Oncology, Vol. 2019The Diagnostic Significance of PDGF, EphA7, CCR5, and CCL5 Levels in Colorectal Cancer9 September 2019 | Biomolecules, Vol. 9, No. 9Exogenous interleukin-1α signaling negatively impacts acquired chemoresistance and alters cell adhesion molecule expression pattern in colorectal carcinoma cells HCT116Cytokine, Vol. 114Maternal stress and early-onset colorectal cancerMedical Hypotheses, Vol. 121Fusobacterium nucleatum Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic AlterationsJournal of the Anus, Rectum and Colon, Vol. 2, No. 2Racial Disparity in Gastrointestinal Cancer RiskGastroenterology, Vol. 153, No. 4 Vol. 13, No. 18 eToC Sign up Follow us on social media for the latest updates Metrics Downloaded 984 times History Published online 22 August 2017 Published in print August 2017 Information© 2017 Future Medicine LtdKeywordscolorectal cancercolorectal cancer molecular subtypeDNA mismatch repairEMASTimmune checkpoint inhibitorimmunotherapyimmunotypingmicrosatellite instabilitypatient outcometumor microenvironmentFinancial & competing interests disclosureThis work was supported by the United States Public Health Service (R01 DK067287, U01 CA162147 and R01 CA206010) and the A Alfred Taubman Medical Research Institute of the University of Michigan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download