Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer

Abstract

Colorectal cancer (CRC) patients, especially those with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) tumors, have derived clinical benefits from immunotherapy. Most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRCs. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC [colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ)] cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI statuses was performed. Compared with CRC patients with MSS/MSI-L tumors, those with MSI-H tumors significantly benefited from ICI treatment. MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes, and higher immunogenicity than MSS/MSI-L CRC. The MANTIS score, which is used to predict the MSI status, was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different immune microenvironments. MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC.

Keywords: Colorectal cancer; colon adenocarcinoma; immune checkpoint inhibitors; microsatellite instability; rectum adenocarcinoma; tumor microenvironment.