Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Immune checkpoint blockade (ICB) efficacy is often predicted by biomarkers like PD-L1, TMB, and MSI.
• Challenges including defining cut-offs and platform variability limit the clinical utility of current biomarkers.
• Novel biomarkers are needed for predicting ICB response.

Purpose of the Study:

• To identify novel biomarkers for predicting ICB efficacy.
• To investigate the association of DNA damage response (DDR) pathway comutations with ICB response and survival outcomes.

Main Methods:

• Analysis of four public clinical cohorts.
• Identification of comutations within homologous recombination repair (HRR) and mismatch repair (MMR) or base excision repair (BER) pathways (co-mut+).
• Assessment of association between co-mut+ status, tumor mutational burden (TMB), neoantigen load, immune gene expression, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Main Results:

• Comutations in HRR-MMR or HRR-BER pathways (co-mut+) were associated with increased TMB and neoantigen load.
• Co-mut+ patients showed increased immune gene expression signatures.
• Co-mut+ patients exhibited higher ORR and improved PFS or OS compared to co-mut- patients.

Conclusions:

• Comutations in specific DDR pathways (HRR-MMR or HRR-BER) serve as potential predictive biomarkers for ICB therapy.
• Identification of DDR comutations offers a convenient approach for estimating TMB and guiding ICB treatment decisions.
• DDR comutations are associated with superior survival outcomes in patients treated with ICB.