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Published on: June 12, 2021
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Persistent mutation burden drives sustained anti-tumor immune responses.
Noushin Niknafs1, Archana Balan1, Christopher Cherry1
1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nature Medicine
|January 26, 2023
Summary
Persistent tumor mutation burden (pTMB), found in stable genomic regions, predicts immunotherapy response. High pTMB indicates a more inflamed tumor microenvironment, suggesting sustained immune control against cancer.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Tumor mutation burden (TMB) is an imperfect predictor of immunotherapy response.
- Predicting treatment efficacy requires better biomarkers for tumor foreignness.
Purpose of the Study:
- To identify a more robust measure of tumor foreignness than TMB.
- To investigate the association of persistent tumor mutation burden (pTMB) with immunotherapy response.
Main Methods:
- Pan-cancer analysis of mutations in 31 tumor types (n=9,242).
- Analysis of eight immunotherapy-treated cohorts (n=524) including non-small cell lung cancer, melanoma, mesothelioma, and head and neck cancer.
- Evaluation of mutations in single-copy and multi-copy genomic regions.
Main Results:
- Persistent tumor mutation burden (pTMB) was defined as mutations in stable genomic regions.
- High pTMB correlated with improved response to immune checkpoint blockade.
- Tumors with high pTMB exhibited inflamed tumor microenvironments and retained mutations under immunotherapy pressure.
Conclusions:
- pTMB is a more consistent predictor of immunotherapy response than TMB.
- pTMB represents an evolutionary bottleneck that cancer cells cannot overcome.
- pTMB may drive sustained immunologic tumor control during immunotherapy.
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