Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade
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AbstractBiomarkers such as programmed death receptor 1 ligand (PD-L1) expression, tumor mutational burden (TMB), and high microsatellite instability are potentially applicable to predict the efficacy of immune checkpoint blockade (ICB). However, several challenges such as defining the cut-off value, test platform uniformity, and low frequencies limit their broad clinical application. Here we identify comutations in the DNA damage response (DDR) pathways of homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER; defined as co-mut+) that are associated with increased TMB and neoantigen load and increased levels of immune gene expression signatures. In four public clinical cohorts, co-mut+ patients presented a higher objective response rate and a longer progression-free survival or overall survival than co-mut- patients. Overall, identification of DDR comutations in HRR-MMR or HRR-BER as predictors of response to ICB provides a potentially convenient approach for future clinical practice.Significance: Identification of comutations in specific DDR pathways as predictors of superior survival outcomes in response to immune checkpoint blockade provide a clinically convenient approach for estimation of tumor mutational burden and delivery of ICB therapy.
All Author(s) ListWang Z, Zhao J, Wang G, Zhang F, Zhang Z, Zhang F, Zhang Y, Dong H, Zhao X, Duan J, Bai H, Tian Y, Wan R, Han M, Cao Y, Xiong L, Liu L, Wang S, Cai S, Mok TSK, Wang J
Journal nameCancer Research
Volume Number78
Issue Number22
Place of PublicationUnited States
Pages6486 - 6496
LanguagesEnglish-United Kingdom
KeywordsImmune Checkpoint Blockade

Last updated on 2020-28-06 at 02:14