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

Abstract

Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic dMMR CRC, 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. Consecutive patients with metastatic dMMR CRC (N=39) treated with anti-PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. 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. Higher MSI burden was associated with improved objective response (P=0.018) and survival. Dichotomized MSI level (Q2-4 vs Q1) was associated with longer PFS (HR, 0.18; 95% 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 diversity were associated with survival. Although HLA-A, -B, -C expression was not prognostic, the HLA-B*07:02 allele was associated with best overall response. In contrast, overexpression of immune exhaustion-related genes and cytotoxic T-cell and NK-cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. 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 between genomic instability, antigen recognition diversity, and immunotherapy benefit.