Immune microenvironment, MSI status, and tumor mutational burden as prognostic factors in colorectal cancer.

Abstract

e14524 Background: Immune checkpoint inhibition has demonstrated meaningful clinical benefit in microsatellite instability–high (MSI-H) colorectal cancer (CRC); however, outcomes remain heterogeneous. The interaction between tumor immune microenvironment features, tumor mutational burden (TMB), and survival outcomes has not been fully characterized. We conducted an integrative analysis of publicly available genomic data to evaluate the prognostic impact of immune infiltration stratified by MSI status and TMB in CRC. Methods: Transcriptomic, somatic mutation, and clinical data for primary colorectal adenocarcinoma were obtained from TCGA-COAD and TCGA-READ. About 600 patients with overall survival data were analyzed. MSI status was taken from TCGA molecular subtype annotations. TMB was defined as the number of nonsynonymous somatic mutations per tumor and dichotomized at the median.Immune infiltration (CD8⁺ and CD4⁺ T cells, macrophages, neutrophils, dendritic cells) was estimated using TIMER. Patients were classified as high or low infiltration by the median. Overall survival was assessed using Kaplan–Meier analysis and Cox models adjusted for age, sex, and tumor stage., and tumor stage. Results: The cohort included approximately 15% MSI-H tumors, which demonstrated significantly higher TMB compared with microsatellite-stable (MSS) tumors. MSI-H tumors exhibited an inflamed immune phenotype, with approximately twofold higher CD8⁺ T-cell infiltration relative to MSS tumors. Across the overall cohort, high CD8⁺ T-cell infiltration was associated with improved OS compared with low infiltration (median OS not reached vs approximately 60–70 months). In contrast, increased macrophage infiltration was associated with inferior survival outcomes. When stratified by genomic features, the favorable prognostic association of CD8⁺ T-cell infiltration was most pronounced in MSI-H and TMB-high tumors, corresponding to an estimated 30–40% relative reduction in mortality risk compared with MSI-H/TMB-high tumors with low immune infiltration. Immune infiltration demonstrated weaker and less consistent associations with OS in MSS/TMB-low tumors. In multivariable analyses, CD8⁺ T-cell infiltration remained independently associated with improved OS after adjustment for clinical covariates, whereas macrophage infiltration remained independently associated with worse outcomes. Findings were consistent across colon and rectal cancer subgroups. Conclusions: In this integrative analysis of TCGA colorectal cancer datasets, features of the tumor immune microenvironment, together with MSI status and TMB, were associated with survival. These results support immune-genomic stratification and suggest that combining immune and molecular biomarkers may improve prognostic assessment and immunotherapy trial design in colorectal cancer.