Replication stress response defects are associated with response to immune checkpoint blockade in non-hypermutated cancers

ABSTRACT: Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with non-hypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrate that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent non-hypermutated cohorts of patients with cancer across 7 tumor types, including those of the breast, prostate, kidney, and brain. Induction or suppression of RSR deficiencies was sufficient to modulate response to ICB in pre-clinical models of breast and renal cancers. Mechanistically, we find that despite robust activation of checkpoint kinase 1 (Chk1) signaling in RSR-deficient cancer cells, aberrant replication origin firing causes exhaustion of replication protein A, resulting in accumulation of immunostimulatory cytosolic DNA. We further found that deficient RSR coincided with increased intratumoral dendritic cells in both mouse cancer models and human tumors. Together, this work demonstrates the RSR defect gene signature can accurately identify patients who may benefit from ICB across numerous non-hypermutated tumor types, and pharmacological induction of RSR defects may further expand the benefits of ICB to more patients. One sentence summary: Endogenous and induced replication stress response defects promote tumor immunogenicity via generation of cytosolic single-stranded DNA.

SUBMITTER: McGrail D 

PROVIDER: S-EPMC8577990 | biostudies-literature |

REPOSITORIES: biostudies-literature