McGrail et al. showed that replication stress response (RSR) defects (RSRD) from aberrant replication origin firing leads to exhaustion of replication protein A pools and accumulation of immunostimulatory cytosolic single-stranded DNA. In preclinical tumor models, restoration of RSR function abrogated response to ICB, and induction of RSRDs sensitized RSRD-low tumors to ICB. A high RSRD gene expression signature predicted functional RSR defects in breast cancer cell lines and correlated with increased dendritic and T cells infiltration in breast cancer and response to ICB in 12 nonhypermutated patient cohorts across seven different tumor types.
Contributed by Shishir Pant
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 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.
Author Info: (1) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Genitourinary Medical Oncology, The University of Te
Author Info: (1) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. (7) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. (8) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. McNair Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. (9) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (10) Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. (11) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (12) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
