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Predictors of Immune Checkpoint Blockade Response in dMMR Colorectal Cancer Using an Integrated Immune-Enhanced Multiomics Platform

Year: 2026

Type: article

Abstract: PURPOSE: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic deficient DNA mismatch repair (dMMR) colorectal cancer, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-related biomarkers associated with clinical outcomes following anti-PD-1 therapy. EXPERIMENTAL DESIGN: Consecutive patients with metastatic dMMR colorectal cancer (N = 39) treated with anti-PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. Microsatellite instability (MSI) burden was quantified as the percentage of unstable microsatellite loci using MSIsensor-pro. Associations with objective response were evaluated, and progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: Higher MSI burden was associated with improved objective response (P = 0.018) and survival. The dichotomized MSI level (Q2-4 vs. Q1) was associated with longer PFS [hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.06-0.56; P = 0.003] and OS (HR, 0.20; 95% CI, 0.07-0.58; P = 0.003), with similar results when modeled continuously. MSI burden correlated with neoantigen clonality but not burden (R = 0.53, P = 0.01). Responders exhibited significantly greater T-cell receptor repertoire diversity; both T- and B-cell receptor diversities were associated with survival. Although human leukocyte antigen (HLA) A, HLA-B, and HLA-C expression was not prognostic, the HLA-B*07:02 allele was associated with the best overall response. In contrast, overexpression of immune exhaustion-related genes and cytotoxic T-cell and natural killer cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. CONCLUSIONS: Integrated exome/transcriptome profiling with MSI quantification identified MSI burden and adaptive immune repertoire diversity as potential correlates of response and survival following ICB. These findings suggest a mechanistic link among genomic instability, antigen recognition diversity, and immunotherapy benefit.

Source: Clinical Cancer Research

DOI: 10.1158/1078-0432.ccr-25-3711