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Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Predictors of Immune Checkpoint Blockade Response in dMMR Colorectal Cancer Using an Integrated Immune-Enhanced
Frank A Sinicrope1,2, Nalin Sharma2, Md Mohiuddin2
1Departments of Oncology and Medicine, Mayo Clinic, Rochester, Minnesota.
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.
Insights
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.
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.
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