What question did this study set out to answer?

To identify biomarkers associated with clinical outcomes in metastatic dMMR CRC after anti–PD-1 therapy.

April 19, 2026

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

Puntos clave

To identify biomarkers associated with clinical outcomes in metastatic dMMR CRC after anti–PD-1 therapy.
Analyzed data from 39 patients with metastatic dMMR CRC treated with anti–PD-1 therapy.
Used immune-enhanced exome and transcriptome profiling for tumor analysis.
Quantified MSI burden with MSIsensor-pro and evaluated associations with response and survival using Cox proportional hazards models.
Higher MSI burden was linked to improved objective response (P=0.018) and better survival outcomes.
Dichotomized MSI levels showed longer progression-free survival (HR 0.18, p=0.003) and overall survival (HR 0.20, p=0.003).
Greater T-cell receptor diversity correlated with survival, while overexpression of immune exhaustion genes indicated resistance to therapy.

Resumen

Abstract Purpose: 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. Methods: 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. Results: 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. 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 between genomic instability, antigen recognition diversity, and immunotherapy benefit.

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