Diverse immune response of DNA damage repair-deficient tumors

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• DNA damage repair (DDR) deficiencies in tumors can lead to neoantigens and increased sensitivity to immune checkpoint inhibitors (ICIs).
• However, a significant proportion of DDR-deficient tumors exhibit resistance to immunotherapy, with the specific mutations driving immunogenicity remaining unclear across different cancer types.

Purpose of the Study:

• To investigate the association between DDR gene mutations, neoantigen load, immune infiltrates, and immunotherapy outcomes across diverse cancer types.
• To identify specific DDR deficiencies that enhance immunogenicity and predict response to immune checkpoint inhibitors.

Main Methods:

• Integrated analysis of somatic and germline mutations and methylation data for DDR genes across 10,080 tumors from 32 cancer types.
• Evaluation of associations between DDR alterations, neoantigen loads, and immune cell infiltrates.
• Assessment of survival outcomes in ICI-treated animal models and human patients.

Main Results:

• Identified specific DDR pathway mutations associated with increased neoantigen loads and adaptive immune markers.
• Demonstrated that distinct DDR deficiencies correlate with specific immune phenotypes, varying by cancer type.
• Observed associations between DDR alterations, immune markers, and improved survival in ICI-treated cohorts.

Conclusions:

• The study provides a comprehensive catalog of DDR deficiencies linked to immune responses, explaining variability in immunotherapy outcomes.
• These findings may facilitate the development of genomic biomarkers to predict immunotherapy response in DDR-deficient cancers.