Replication Stress Response Defects Are Associated With Response to Immune Checkpoint Blockade in Nonhypermutated Cancers

Authors

Daniel J McGrail
Patrick G Pilié
Hui Dai
Truong Nguyen Anh Lam
Yulong Liang
Leonie Voorwerk
Marleen Kok
Xiang H-F Zhang
Jeffrey M Rosen
Amy B Heimberger
Christine B Peterson
Eric Jonasch
Shiaw-Yih Lin

Publication Date

10-27-2021

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.abe6201

PMID

34705519

PMCID

PMC8577990

PubMedCentral® Posted Date

11-10-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Immune Checkpoint Inhibitors, Neoplasms

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.

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