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.

Correlations Between Tumor Mutation Burden and Immunocyte Infiltration and Their Prognostic Value in Colon Cancer

“…As additional bases insertion or existing bases deletion from microsatellites, DNA mismatch errors occur during DNA replication, which can be supervised and corrected by the MMR system ( Arana and Kunkel, 2010 ). For patients with MMR deficiency (dMMR), accumulated mismatch mutation and frameshift mutation will lead to the MSI phenotype, neoantigens production, and is related to carcinogenesis of several cancers, such as CRC, gastric cancer, pancreatic cancer, and endometrial cancer ( Palomaki et al, 2009 ; Seo et al, 2009 ; Ghidini et al, 2020 ; Lin et al, 2020 ). In CRC, dMMR or high levels of MSI (MSI-H) were correlated with high TMB and immunocyte infiltration, which made dMMR-MSI-H CRC responsible for ICBs ( Alexander et al, 2001 ; Llosa et al, 2015 ; Ganesh et al, 2019 ).…”

The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

“…Recent studies have demonstrated that a 'mutator phenotype' associated with loss of mismatch repair pathways is a stronger predictor of outcome than quantity of mutations (109,110). Such tumors have increased T cell infiltrates counterbalanced by local immune suppression, including increased PDL1 expression (109,(111)(112)(113). However, it is unclear whether the mutations in these tumors dictates this infiltration phenotype.…”

Relationship between microsatellite status and immune microenvironment of colorectal cancer and its application to diagnosis and treatment

“…[17][18][19][20][21] The same types of tumors have different biological characteristics and different immune microenvironments, as is the case for colorectal and rectal cancers. 22 These differences directly affect responses to ICI treatment. [23][24][25][26] The main differences in the tumor microenvironments (TMEs) of dMMR/MSI-H, and pMMR/ MSS CRC patients are described below (Figure 1).…”