Immune checkpoint blockade (ICB) produces durable responses on difficult-to-treat tumors, but its effects are heterogeneous on patients. DNA damage response (DDR) is a network of multiple functional pathways to maintain genomic stability, and mutations in DDR genes are a major determinant of response to ICB. However, only a subset of DDR-altered patients benefit from ICB, and their responses vary across cancer types.
This is a retrospective pan-cancer study. We assessed the prognostic value of pre-defined core DDR pathways in 1571 patients derived from cBioPortal TMB/Immunotherapy datasets. 7417 treatment-naïve Chinese patients that underwent targeted next-generation sequencing were then used to compare genomic profiles between DDR proficient and deficient samples. Furthermore, we calculated the tumor-infiltrating lymphocyte (TIL) scores of 3164 samples derived from TCGA transcriptome datasets to evaluate the tumor environment (TME) with different types of DDR status.
DDR deficient patients from cBioPortal showed significantly higher tumor mutation burden (TMB, p<0.001) and better ICB overall survival (34 vs 17 months, p=0.001) than DDR proficient. Among the DDR pathways, only damage sensing is an independent prognostic factor for the overall survival of ICB treatment (HR, 0.66; 95%CI, 0.44-0.99). The DDR deficient patients account for 14.5% of our Chinese cohort. Their TMB and microsatellite instability (MSI) ratio varied significantly from DDR proficient samples (p<0.001). Comparison between defects in damage sensing and other DDR pathways showed no remarkable difference in TMB and MSI (p=0.879 and 0.082, respectively), but a set of cancer-related genes involved in modulating TME were differentially mutated. In the TCGA datasets, defects in damage sensing but not other DDR pathways are associated with significantly increased TIL scores than DDR proficiency (p= 0.032 and 0.192, respectively).
Damage sensing deficiency is associated with a favorable prognosis of ICB. The underlying mutations may synergistically modulate the TME. The prognostic role of DNA damage sensing may provide insights into current biomarkers and help stratify DDR-deficient patients for ICB treatment.
Clinical trial identification
Legal entity responsible for the study
Has not received any funding.
Y. Shao, X. Chen, X. Wu, Q. Ou, J. Yin, X. Wu: Financial Interests, Personal, Full or part-time Employment: Nanjing Geneseeq Technology Inc.