Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers
Menée à partir de données portant sur des patients atteints d'une tumeur ne présentant pas d'hypermutation et menée à l'aide de modèles murins de cancer, cette étude met en évidence une association entre une signature génétique, révélant une déficience au niveau de la réponse au stress de réplication de l'ADN, et la réponse des cellules cancéreuses aux inhibiteurs de point de contrôle immunitaire
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 nonhypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrated that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent cohorts of patients with nonhypermutated cancer across seven 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 preclinical models of breast and renal cancers. Mechanistically, we found that despite robust activation of checkpoint kinase 1 signaling in RSR-deficient cancer cells, aberrant replication origin firing caused 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 that the RSR defect gene signature can accurately identify patients who may benefit from ICB across numerous nonhypermutated tumor types, and pharmacological induction of RSR defects may further expand the benefits of ICB to more patients.
Science Translational Medicine , résumé, 2020