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

Abstract

Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n ¼ 13) versus those who did not (n ¼ 6) to anti-PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n ¼ 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. Results: Although both IL17 Low and IL17 High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/ IFNg and PD-L1/IDO1 colocalization), only IL17 Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. Conclusions: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy. See related commentary by Willis et al., p. 5185

Deep immunophenotyping at the single-cell level identifies a combination of anti-IL-17 and checkpoint blockade as an effective treatment in a preclinical model of data-guided personalized immunotherapy

“… 28 As Coffelt et al 16 reported, IL-17 producing γδ T cells and neutrophils suppressed cytotoxic CD8 + T cells and promoted breast cancer metastasis; IL-17 is now being examined as a cause of tumor progression and resistance to therapy. It has been reported that IL-17 signature was associated with the resistance to anti-PD-1 therapy in colorectal cancer 29 and melanoma. 30 In this preclinical model, we identified CD4 + T cells and γδ T cells in the tumor produced IL-17.…”

Microsatellite instability: a review of what the oncologist should know

“…demonstrated that the immune blocking effect of the tumor itself is great relative to generate immunosuppressive microenvironment. Llosa et al found that this immune function is caused by the upregulation of several checkpoint ligands, among which PD-1/PD-L1 is an important ligand[66]. The prognosis of early Endometrial Carcinoma (EC) is not correlated with MSI[67], but the results of EC in the middle and late stage were opposite.…”

Regulatory T cells specifically suppress conventional CD8αβ T cells in intestinal tumors of APCMin/+ mice

“…Notably, the γδT17 cells in human CRC also produced TNF, but were not cytotoxic. Given the observations that Th17-type immunity is detrimental in CRC [10,40], γδT17 cells may also contribute significantly to poor patient outcome [41,42]. Here, we show that TCRγδCD8 − T cells are indeed a major source of IL-17A and TNF in the tumors of APC Min/+ mice and that they represent an adequate model of human CRC also in this aspect.…”

“…Generally, this relatively short PD-1 antibody treatment did not affect immune responses or tumor growth in APC Min/+ mice. This may be caused by the pre-existing γδT17 cells response, as Th17-like responses were recently shown to limit the benefit of PD-1 antibody treatment in MSS CRC [40].…”