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Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations

Moh'd M Khushman1, Michael D Toboni2, Joanne Xiu3

  • 1Washington University in St. Louis/Siteman Cancer Center, St. Louis, Missouri.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 13, 2024
PubMed
Abstract

Insights

Patients with mutS co-loss alterations in colorectal and endometrial cancers show improved survival and better response to immune checkpoint inhibitors (ICI). Neoantigen load (NAL) may drive these outcomes, as tumor mutation burden (TMB) did not reliably predict NAL.

Area of Science:

  • Oncology
  • Immunotherapy
  • Genomics

Background:

  • Response to immune checkpoint inhibitors (ICI) in mismatch repair deficient (dMMR) colorectal and endometrial cancers is variable.
  • Understanding differential responses based on specific mismatch repair alterations is crucial for optimizing treatment.

Purpose of the Study:

  • To investigate the differential response to ICIs in dMMR colorectal and endometrial cancers based on distinct mismatch repair alterations.
  • To explore the association between specific mismatch repair gene co-loss (mutS vs. mutL) and clinical outcomes, including overall survival and neoantigen load.

Main Methods:

  • Analysis of 13,701 colorectal cancer and 3,315 endometrial cancer specimens.
  • Estimation of median overall survival (mOS) using Kaplan-Meier analysis.
  • Assessment of neoantigen load (NAL) and prediction of epitopes by tumor mutation burden (TMB) using R-squared values.

Main Results:

  • MutS (MSH2/MSH6) co-loss was associated with significantly longer mOS compared to MutL (MLH1/PMS2) co-loss in both colorectal (54.6 vs. 36 months) and endometrial cancers (81.5 vs. 48.2 months).
  • In ICI-treated patients, MutS co-loss correlated with longer mOS in colorectal cancer (NR vs. 36 months).
  • Higher NAL was observed in MutS co-loss compared to MutL co-loss across both cancer types, suggesting NAL as a potential driver of improved outcomes. TMB did not reliably predict NAL.

Conclusions:

  • MutS co-loss is linked to superior overall survival and enhanced response to ICIs in colorectal cancer.
  • Neoantigen load (NAL) appears to be a key factor contributing to better outcomes in patients with MutS co-loss.
  • Tumor mutation burden (TMB) is not a reliable predictor of NAL in this context.

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