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      Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors

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          Abstract

          Approximately 10% of mismatch repair proficient (MMRp) colorectal cancer (CRC) patients showed clinical benefit to anti-PD-1 monotherapy ( ). We sought to identify biomarkers that delineate patients with immunoreactive CRC and to explore new combinatorial immunotherapy strategies that can impact MMRp CRC. We compared the expression of 44 selected immune-related gene expression in the primary colon tumor of 19 metastatic CRC patients who responded (n=13) versus those who did not (n=6) to anti PD-1 therapy ( ). We define a 10 gene-based immune signature that could distinguish responder from non-responder. Resected colon specimens (n=14) were used to validate the association of the predicted status (responder and non-responder) with the immune related gene expression, the phenotype and the function of tumor-infiltrating lymphocytes (TILs) freshly isolated from the same tumors. Although both IL-17 Low and IL17 High immunoreactive MMRp CRC are associated with intratumor correlates of adaptive immunosuppression (CD8/IFNγ and PD-L1/IDO1 colocalization), only IL-17 Low MMRp tumors (3 out of 14) have a tumor immune microenvironment (T i ME) that resembles the T i ME in primary colon tumors of metastatic CRC patients responsive to anti-PD1 treatment. The detection of a preexisting anti-tumor immune response in MMRp CRC (immunoreactive MMRp CRC) is not sufficient to predict a clinical benefit to T cell checkpoint inhibitors. Intra-tumoral IL-17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL-17 signaling pathway are available in clinic and their combination with T cell checkpoint inhibitors could improve CRC immunotherapy.

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          Author and article information

          Journal
          Clinical Cancer Research
          Clin Cancer Res
          American Association for Cancer Research (AACR)
          1078-0432
          1557-3265
          September 03 2019
          September 01 2019
          September 01 2019
          May 06 2019
          : 25
          : 17
          : 5250-5259
          Article
          10.1158/1078-0432.CCR-19-0114
          6726531
          31061070
          130338f1-6534-4d2f-86f3-d6cce6dea46c
          © 2019
          History

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