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

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Immune checkpoint blockade (ICB) shows efficacy in metastatic deficient mismatch repair colorectal cancer (dMMR CRC).
• However, significant molecular heterogeneity and resistance to ICB persist.
• Identifying biomarkers is crucial for predicting patient response to anti-PD-1 therapy.

Purpose of the Study:

• To identify tumor and immune biomarkers associated with clinical outcomes in metastatic dMMR CRC patients treated with anti-PD-1 therapy.
• To investigate the relationship between microsatellite instability (MSI) burden, immune repertoire diversity, and response to immunotherapy.
• To explore potential mechanisms linking genomic instability and immunotherapy benefit.

Main Methods:

• Utilized an immune-enhanced exome and transcriptome platform for tumor profiling in 39 metastatic dMMR CRC patients.
• Quantified MSI burden using MSIsensor-pro.
• Analyzed associations with objective response, progression-free survival (PFS), and overall survival (OS) using Cox proportional hazards models.

Main Results:

• Higher MSI burden correlated with improved objective response and survival.
• Increased T-cell and B-cell receptor repertoire diversity were associated with better survival.
• Overexpression of immune exhaustion markers was linked to ICB resistance and poorer prognosis.
• The HLA-B*07:02 allele was associated with the best overall response.

Conclusions:

• Integrated profiling identified MSI burden and adaptive immune repertoire diversity as potential biomarkers for ICB response and survival in dMMR CRC.
• Findings suggest a mechanistic link between genomic instability, antigen recognition diversity, and immunotherapy efficacy.
• These biomarkers could aid in patient selection for anti-PD-1 therapy.