Abstract 2793: Mismatch repair proficient colorectal cancer and adaptive immunosuppression of endogenous anti-tumor immune response: Implications for immunotherapy

Abstract The tumor immune microenvironment (TiME) of mismatch-repair deficient (MMRd) colorectal cancer (CRC) is characterized by a cytotoxic T cell immune signature and counter-expression of IFNγ -inducible T cell checkpoints, features underlining intratumoral adaptive immunosuppression and sensitivity to immune checkpoint blockade. Since single-agent checkpoint inhibitors have not demonstrated, so far, similar meaningful clinical activity for MMR proficient (MMRp) CRC, we compared the tumor immune microenvironment (TiME) in CRC patients that responded to anti-PD1 therapy with the TiME of patients that did not (NCT01876511) to identify immune signatures and biomarkers that could help deciding on combinatorial immunotherapies to treat patients with MMRp CRC. With this approach, we detected immunoreactive MMRp (irMMRp) tumors characterized by a dense infiltration with cytotoxic T cells (CTL) as well as high expression of IFNγ and CD274 (PD-L1), despite their low tumor mutation burden. We observed that these irMMRp colon tumors are characterized by a negative association between Indolamine 2,3 dioxygenase 1 (IDO1) expression and Th17 infiltration. Despite the high expression of CD8 and PD-L1 expression, only irMMRp CRC with high expression of IDO1 on tumor cells and low infiltration with Th17 cells have a TiME resembling the TiME of CRC responding to anti-PD1. Since IDO1-derived tryptophan metabolites, kynurenines, are known to repress Th17 differentiation, these results suggested that the use of IDO1 small molecule inhibitors may derepress Th17 infiltration in CRC and blunt the effect of anti-PD1. Combining therapy with IDO1/PD1 inhibitors with drugs inhibiting IL-17 signaling pathway may help to treat irMMRp CRC patients. Citation Format: Nicolas Llosa, Anas H. Awan, Ada J. Tam, Hongni Fan, Kellie N. Smith, Cynthia L. Sears, Hao Wang, Drew M. Pardoll, Robert A. Anders, Franck Housseau. Mismatch repair proficient colorectal cancer and adaptive immunosuppression of endogenous anti-tumor immune response: Implications for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2793.