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Microsatellite instability (MSI) burden and diverse immune cell receptors predict response to anti-PD-1 therapy in metastatic deficient mismatch repair colorectal cancer (dMMR CRC). Higher MSI burden and immune diversity correlate with better survival outcomes.

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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.