Immunotherapy in the treatment of colorectal cancer: a new kid on the block

Abstract

In the last few years, the success of anti-PD1 and anti-PDL1 drugs in solid cancers treatment and the advances in molecular biology have provided new potential treatment strategies for patients with metastatic colorectal cancer. Unfortunately, only patients with mismatch repair deficiency seem to benefit from immunotherapy and they represent a small subset of the metastatic population. New ongoing studies focus on converting an immune ignorant tumour into an inflamed one by combination therapies and on introducing an immunotherapeutic approach in earlier stages of disease (neoadjuvant and adjuvant setting). In this review we summarize the current knowledge about the molecular and immune landscape of colorectal cancer and propose new potential combination strategies to enhance the efficacy of immunotherapy.

Keywords

Colorectal cancer / immunotherapy / microsatellite instability / pembrolizumab / nivolumab / atezolizumab

References

[1] Siegel RL,Fedewa SA,Meester RGS,Jemal A.Colorectal cancer statistics, 2017.CA Cancer J Clin2017;67:177-93

[2] Arnold M,Laversanne M,Jemal A.Global patterns and trends in colorectal cancer incidence and mortality.Gut2017;66:683-91

[3] Welch HG.Colorectal cancer on the decline--why screening can't explain it all.N Engl J Med2016;374:1605-7

[4] Cremolini C,Antoniotti C,Salvatore L,Falcone A.First-line chemotherapy for mCRC-a review and evidence-based algorithm.Nat Rev Clin Oncol2015;12:607-19

[5] Roelands J,Vermeulen L,Decock J,Marincola FM,Hendrickx W.Immunogenomic classification of colorectal cancer and therapeutic implications.Int J Mol Sci2017;18:E2229 PMCID:PMC5666908

[6] Guinney J,Wang X,Schlicker A,Marisa L,Nyamundanda G,Bot BM,Simon IM,Fessler E,Missiaglia E,Barras D,Maru D,Broom B,Perez-Villamil B,Salazar R,Hanahan D,Bernards R,Laurent-Puig P,Sadanandam A,Delorenzi M,Vermeulen L.The consensus molecular subtypes of colorectal cancer.Nat Med2015;21:1350-6 PMCID:PMC4636487

[7] Markman JL.Impact of the immune system and immunotherapy in colorectal cancer.J Gastrointest Oncol2015;6:208-23 PMCID:PMC4311093

[8] Burnet FM.The concept of immunological surveillance.Prog Exp Tumor Res1970;13:1-27

[9] Dunn GP,Schreiber RD.The three Es of cancer immunoediting.Annu Rev Immunol2004;22:329-60

[10] Schreiber RD,Smyth MJ.Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.Science2011;331:1565-70

[11] Grizzi F,Borroni EM,Bianchi P,Chiriva-Internati M,Laghi L.Evolving notions on immune response in colorectal cancer and their implications for biomarker development.Inflamm Res2018;67:375-89

[12] Cancer Genome Atlas Research Network..Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014;513:202-9 PMCID:PMC4170219

[13] Blank C,Mackensen A.Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy.Cancer Immunol Immunother2005;54:307-14

[14] Haqq J,Garcea G,Steward WP.Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies.Eur J Cancer2014;50:2570-82

[15] Mueller MM.Friends or foes - bipolar effects of the tumour stroma in cancer.Nat Rev Cancer2004;4:839-49

[16] Herrera M,Dominguez G,Garcia V,Gomez I,Munoz C,Campos-Martin Y,Casal I,Pena C.Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients.Cancer Sci2013;104:437-44

[17] Fridman WH,Sautes-Fridman C.The immune contexture in human tumours: impact on clinical outcome.Nat Rev Cancer2012;12:298-306

[18] Chen J.The effect of immune microenvironment on the progression and prognosis of colorectal cancer.Med Oncol2014;31:82

[19] Galon J,Bindea G,Berger A,Lugli A,Hartmann A,Nagtegaal ID,Masucci GV,Tatangelo F,Maio M,Grizzi F,D'Arrigo C,Zavadova E,Ohashi PS,Wouters BG,Nguyen L,Hazama S,Ogino S,Waring P,Torigoe T,Patel PS,Wang Y,Sinicrope FA,Ascierto PA,Fox BA.Towards the introduction of the 'Immunoscore' in the classification of malignant tumours.J Pathol2014;232:199-209 PMCID:PMC4255306

[20] Mlecnik B,Kirilovsky A,Obenauf AC,Church SE,Vasaturo A,Fredriksen T,Waldner M,Speicher MR,Valge-Archer V.The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis.Sci Transl Med2016;8:327ra26

[21] Fearon ER.A genetic model for colorectal tumorigenesis.Cell1990;61:759-67

[22] Vogelstein B,Velculescu VE,Diaz LAJr.Cancer genome landscapes.Science2013;339:1546-58 PMCID:PMC3749880

[23] Issa JP.CpG island methylator phenotype in cancer.Nat Rev Cancer2004;4:988-93

[24] Jones PA.The fundamental role of epigenetic events in cancer.Nat Rev Genet2002;3:415-28

[25] Armaghany T,Chu Q.Genetic alterations in colorectal cancer.Gastrointest Cancer Res2012;5:19-27 PMCID:PMC3348713

[26] Gruber SB.The genetics of hereditary non-polyposis colorectal cancer.J Natl Compr Canc Netw2003;1:137-44

[27] Gelsomino F,Spallanzani A,Cascinu S.The evolving role of microsatellite instability in colorectal cancer: a review.Cancer Treat Rev2016;51:19-26

[28] Boland CR,Hamilton SR,Eshleman JR,Meltzer SJ,Fodde R,Srivastava S.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 Res1998;58:5248-57

[29] Roepman P,Tabernero J,Tian S,Snel MH,Rosenberg R,Macarulla T,Salazar R,Wessels LF,Simon IM.Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition.Int J Cancer2014;134:552-62 PMCID:PMC4234005

[30] Budinska E,Tejpar S,Lapique N,Di Narzo AF,Hodgson JG,Bosman F,Delorenzi M.Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.J Pathol2013;231:63-76 PMCID:PMC3840702

[31] Schlicker A,Chresta CM,Pritchard A,Runswick S,Heathcote K,Orphanides G,Wessels LF.Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines.BMC Med Genomics2012;5:66 PMCID:PMC3543849

[32] Sadanandam A,Homicsko K,Gibb WJ,Ostos LC,Grotzinger C,Lhermitte B,Wiedenmann B,Gray JW.A colorectal cancer classification system that associates cellular phenotype and responses to therapy.Nat Med2013;19:619-25 PMCID:PMC3774607

[33] Marisa L,Duval A,Gaub MP,Etienne-Grimaldi MC,Guenot D,Kirzin S,Flejou JF,Berger A,Pencreach E,Elias D,Olschwang S,Laurent-Puig P.Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.PLoS Med2013;10:e1001453 PMCID:PMC3660251

[34] De Sousa EMF,Jansen M,Trinh A,de Jong JH,van Leersum R,Rodermond H,van Noesel CJ,Dekker E,Medema JP.Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions.Nat Med2013;19:614-8

[35] Llosa NJ,Tam A,Hechenbleikner EM,Blosser RL,Wang H,Zhang M,Kinzler KW,Sears CL,Pardoll DM.The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints.Cancer Discov2015;5:43-51 PMCID:PMC4293246

[36] Tran B,Tie J,Jiang ZQ,Agarwal A,Sieber O.Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer.Cancer2011;117:4623-32 PMCID:PMC4257471

[37] Gavin PG,Fumagalli D,Remillard MY,Kim C,Kim SI,Blackmon NL,Petrelli NJ,Wolmark N,Pogue-Geile KL.Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.Clin Cancer Res2012;18:6531-41 PMCID:PMC4273673

[38] Popovici V,Bosman FT,Roth AD.Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer.BMC Cancer2013;13:439 PMCID:PMC3849526

[39] Colle R,Cochereau D,Lascols O,Afchain P,Parc Y,Flejou JF,Andre T.Immunotherapy and patients treated for cancer with microsatellite instability.Bull Cancer2017;104:42-51

[40] Lenz HJ,Venook AP,Niedzwiecki D,Mayer RJ,Blanke CD,Qu X,Kabbarah O.Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance)..J Clin Oncol2017;35 Suppl 15:abstr3511

[41] Chung KY,Fong L,Beck SB,Criscitiello PJ,Huang B,Saltz LB.Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer.J Clin Oncol2010;28:3485-90

[42] Le DT,Wang H,Kemberling H,Skora AD,Azad NS,Biedrzycki B,Zaheer A,Crocenzi TS,Duffy SM,de la Chapelle A,Bhaijee F,Hruban RH,Cuka N,Papadopoulos N,Zhou S,Taube JM,Eshleman JR,Diaz LA, Jr..PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[43] Overman MJ,Leach JL,Lenz HJ,Desai J,Axelson M,Goldberg MV,Ledeine JM,Kopetz S.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 Oncol2017;18:1182-91

[44] Overman MJ,Wong KYM,Gelsomino F,Morse MA,McDermott R,Sawyer MB,Neyns B,Moss RA,Cao ZA,Kopetz S.Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.J Clin Oncol2018;36:773-9

[45] Topalian SL,Brahmer JR,Smith DC,Powderly JD,Sosman JA,Leming PD,Antonia SJ,Drake CG,Chen L,Anders RA,McMiller TL,Korman AJ,Agrawal S,Kollia GD,Wigginton JM.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med2012;366:2443-54 PMCID:PMC3544539

[46] Brahmer JR,Chow LQ,Topalian SL,Drake CG,Kauh J,Pitot HC,Bhatia S,Eaton K,Salay TM,Grosso JF,Parker SM,Goldberg SM,Gupta A.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med2012;366:2455-65 PMCID:PMC3563263

[47] Dienstmann R,Guinney J,Tejpar S.Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer.Nat Rev Cancer2017;17:268

[48] Schaer DA,Wolchok JD.Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.J Immunother Cancer2014;2:7 PMCID:PMC4030310

[49] Bendell JC,Lieu CH,Hurwitz H,Murphy JE,Rossi C,Waterkamp D.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 Oncol2015;33 Suppl 3:abstr704

[50] Limagne E,Thibaudin M,Derangere V,Boidot R,Bonnefoy N,Bengrine-Lefevre L,Delmas D,Ghiringhelli F.Accumulation of MDSC and Th17 cells in patients with metastatic colorectal cancer predicts the efficacy of a FOLFOX-bevacizumab drug treatment regimen.Cancer Res2016;76:5241-52

[51] Ebert PJR,Yang Y,Hong R,Gould SE,Irving BA,Belvin M.MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade.Immunity2016;44:609-21

[52] Hatzivassiliou G,Chen H,Price S,Hewitt JF,Peck A,Merchant M,Chan J,Anderson DJ,Wiesmann C,Friedman LS,Belvin M.Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.Nature2013;501:232-6

[53] Bendell JC,Goh BC,Oh DY,Lee CB,Desai JM,Solomon BJ,Miller WH,Flaherty K,Das-Thakur M,Cha E.Clinical activity and safety of cobimetinib and atezolizumab in colorectal cancer.J Clin Oncol2016;34 Suppl 15:abstr3502

[54] Zheng H,Yan C,Massengill M,Massengill C,Martinez GV,Chen Z,Antonia SJ,Ruffell B.HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma.Clin Cancer Res2016;22:4119-32 PMCID:PMC4987196

[55] Bacac M,Sam J,Weinzierl T,Bodmer W,Hofer T,Moessner E,Bruenker P,Schaller T,Gerdes C,Nicolini V,Dudal S,von Hirschheydt T,Saro J,Klein C.A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors.Clin Cancer Res2016;22:3286-97

[56] Bacac M,Umana P.CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors.Oncoimmunology2016;5:e1203498 PMCID:PMC5007959

[57] Tabernero J,Ros W,Marabelle A,Albanell J,Moreno V,Eder JP,Bouseida S,Sabanes D,Hurwitz H,Saro Suarez JM.Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC)..J Clin Oncol2017;35 Suppl 15:abstr3002

[58] Mole RH.Whole body irradiation; radiobiology or medicine?.Br J Radiol1953;26:234-41

[59] Sharma A,Wenger RH,Sartori AA,Knuth A,Broek M.Gamma-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo.PLoS One2011;6:e28217 PMCID:PMC3226680

[60] Park SS,Liu X,Krco CJ,Mansfield AS,Olivier KR.PD-1 restrains radiotherapy-induced abscopal effect.Cancer Immunol Res2015;3:610-9 PMCID:PMC4827718

[61] Segal NH,Cercek A,Raasch PJ,Hrabovsky AE,Shia J,Erinjeri JP,Yamada Y.Non-randomized phase II study to assess the efficacy of pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) patients.J Clin Oncol2016;34 Suppl 15:abstr3539

[62] Beatty GL,Clark J,Bowman KJ,Newton RC,Maleski J,Gajewski TF.First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies.Clin Cancer Res2017;23:3269-76

[63] Gangadhar TC,Smith DC,Wasser AC,Luke JJ,Kaufman DR,Maleski J,Leopold L Gajewski TF.Epacadostat plus pembrolizumab in patients with advance melanoma and select solid tumors: Updated phase 1 results from ECHO-202/KEYNOTE-037.Ann Oncol2016;27 suppl 6:1110PD

[64] Srivastava RM,Andrade Filho PA,Jie HB,Lopez-Albaitero A,Gooding WE,Ferris RL.Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.Clin Cancer Res2013;19:1858-72 PMCID:PMC3640274

[65] Basile D,Bonotto M,Casagrande M,Fanotto V,Loupakis F,Negri FV,Russano M,Scartozzi M,Silvestris N,Puzzoni M,Cardarelli N.Immunotherapy for colorectal cancer: where are we heading?.Expert Opin Biol Ther2017;17:709-21

[66] Wittig B,Scheithauer W.MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: from bench to bedside.Crit Rev Oncol Hematol2015;94:31-44

[67] Schmoll HJ,Arnold D,Nitsche D,Mayer F,Ziebermayr R.Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial.J Cancer Res Clin Oncol2014;140:1615-24 PMCID:PMC4131138

[68] Brivio F,Alderi G,Lavorato F.Preoperative interleukin-2 subcutaneous immunotherapy may prolong the survival time in advanced colorectal cancer patients.Oncology1996;53:263-8

[69] Kimura T,Dzubinski LA,Potter DM,Schoen RE.MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study.Cancer Prev Res (Phila).2013;6:18-26 PMCID:PMC3536916

[70] Carbone DP,Kelley MJ,Nadaf S,Maher VE,Contois D,Pendleton CD,Carter C,Greenblatt J,Kelsey MI,Berzofsky JA.Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome.J Clin Oncol2005;23:5099-107

[71] Fletcher R,Schoen RE,Yu J.Colorectal cancer prevention: Immune modulation taking the stage.Biochim Biophys Acta2018;1869:138-48

[72] Frouws MA,Maas HA,Portielje JEA,Bastiaannet E.The mortality reducing effect of aspirin in colorectal cancer patients: Interpreting the evidence.Cancer Treat Rev2017;55:120-7

[73] Zelenay S,Bottcher JP,Rogers N,Chakravarty P,Marais R,Sahai E.Cyclooxygenase-dependent tumor growth through evasion of immunity.Cell2015;162:1257-70 PMCID:PMC4597191

[74] Ogino S,Hamada T,Peters U,Giovannucci EL,Giannakis M,Song M.Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine.Gut2018;67:1168-80

[75] Sivan A,Hubert N,Aquino-Michaels K,Benyamin FW,Jabri B,Chang EB.Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science2015;350:1084-9 PMCID:PMC4873287

[76] Vetizou M,Daillere R,Waldschmitt N,Rusakiewicz S,Roberti MP,Poirier-Colame V,Becharef S,Golden E,Eberl G,Ginhoux F,Yamazaki T,Enot DP,Nigou J,Eggermont A,Chachaty E,Robert C,Kroemer G,Boneca IG,Chamaillard M.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science2015;350:1079-84 PMCID:PMC4721659

[77] Yu T,Yu Y,Ma D,Qian Y,Sun D,Chen Y,Hong J,Fang JY.Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy.Cell2017;170:548-63.e16 PMCID:PMC5767127

[78] Gopalakrishnan V,Nezi L,Andrews MC,Prieto PA,Hoffman K,Cogdill AP,Hudgens CW,Manzo T,Cotechini T,Chen WS,Szczepaniak Sloane R,Jiang H,Shpall EJ,Alousi AM,Shelburne S,Okhuysen PC,Swennes AG,Marcelo Riquelme Sanchez E,Le Chatelier E,Pons N,Haydu LE,Gardner JM,Hu J,Tsujikawa T,Tawbi H,Hwu WJ,Woodman SE,Davies MA,Hwu P,Zhang J,Cooper ZA,Daniel CR,Petrosino JF,Sharma P,Jenq RR.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science2018;359:97-103 PMCID:PMC5827966

[79] Rajpoot M,Sharma A.Understanding the microbiome: emerging biomarkers for exploiting the microbiota for personalized medicine against cancer.Semin Cancer Biol2018;

[80] Routy B,Derosa L,Alou MT,Fluckiger A,Rauber C,Fidelle M,Poirier-Colame V,Klein C,Mondragon L,Qu B,Clemenson C,Masip JR,Brosseau S,Richard C,Levenez F,Quinquis B,Ryffel B,Gonin P,Deutsch E,Ghiringhelli F,Goldwasser F,Hellmann MD,Raoult D,Kroemer G.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science2018;359:91-7

[81] Andre T,Vernerey D,Bonnetain F,Scriva A,Tabernero J,Banzi M,Shmueli E,Scheithauer W,Moehler M,Demetter P,Tournigand C,Duval A,de Gramont A.Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study.J Clin Oncol2015;33:4176-87

[82] Shin DS,Escuin-Ordinas H,Hu-Lieskovan S,Grasso CS,Sandoval S,Palaskas N,Parisi G,Chmielowski B,Seja E,Shintaku IP,Pardoll DM,Tumeh PC,Lo RS,Ribas A.Primary resistance to PD-1 blockade mediated by JAK1/2 mutations..Cancer Discov2017;7:188-201 PMCID:PMC5296316

[83] Petrelli F,Borgonovo K,Turati L,Passalacqua R,Barni S.Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis.JAMA Oncol2016;

[84] Tejpar S,Ciardiello F,Van Cutsem E,Esser R,Heinemann V.Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials.JAMA Oncol2016;

[85] Seligmann JF,Richman SD,Hemmings G,Barrett JH,Quirke P.Combined epiregulin and amphiregulin expression levels as a predictive biomarker for panitumumab therapy benefit or lack of benefit in patients with RAS wild-type advanced colorectal cancer.JAMA Oncol2016;

[86] Song N,Gavin PG,Kim SR,Lipchik C,Petrelli NJ,Wolmark N.Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial.JAMA Oncol2016;2:1162-9 PMCID:PMC5065181

[87] Corcoran RB,Falchook GS,Ryan DP,Hamid O,Daud A,Pierobon M,Cunningham E,Orford K,Bai Y,Venook AP.Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer.J Clin Oncol2015;33:4023-31 PMCID:PMC4669588

[88] Kopetz S,Morris VK,Magliocco AM,Diaz LA,Wang SE,Eckhardt SH,Kaberle K,Hochster HS.Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406)..J Clin Oncol2017;35 suppl 15:abstr520

[89] Triplett TA,Triplett KC,Sun L,Akporiaye ET.STAT3 signaling is required for optimal regression of large established tumors in mice treated with anti-OX40 and TGFbeta receptor blockade.Cancer Immunol Res2015;3:526-35

[90] Teufel M,Seidel H,Reischl J,Lenz HJ,Siena S,Van Cutsem E,Wilhelm S,Laurent D,Rutstein MD,Guinney J.Molecular subtypes and outcomes in regorafenib-treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial.J Clin Oncol2015;33 Suppl 15:abstr4000

[91] Wang G,Dey P,Wu CC,Fang Z,Konaparthi R,Zhang J,Kapoor A,Patel NB,Ramamoorthy V,Heffernan T,Shang X,Hou P,Jin EJ,Pan X,Shi Y,Chang Q,Logothetis CJ,Chin L,DePinho RA.Targeting YAP-dependent MDSC infiltration impairs tumor progression.Cancer Discov2016;6:80-95 PMCID:PMC4707102