ArticleScience translational medicine2021
Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Axitinib plus Avelumab in Recurrent/Metastatic Adenoid Cystic Carcinoma: Biomarker Analysis and Updated Results of the Phase II Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
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- Chemotherapeutic induction of cytosolic single-stranded DNA accumulation sensitizes triple-negative breast cancer to immunotherapy.Journal for immunotherapy of cancer · 2026Article
- Phase 1 study of ceralasertib, an ATR kinase inhibitor, in combination with durvalumab in patients with recurrent or metastatic NSCLC or HNSCC.British journal of cancer · 2026Article
- Targeting RNase H2: A dual-mechanism strategy to elevate replication stress, DNA damage, and antitumor immunity in TNBC.Cell reports. Medicine · 2026Article
- Biomarkers of immunotherapy response in neuro-oncology.Neuro-oncology advances · 2025Review
- CHK1 inhibition increases the therapeutic response to radiotherapy via antitumor immunity in ARID1A-deficient colorectal cancer.Cell death & disease · 2025Article
- Complex rearrangements fuel ERNature · 2025Article
- Glioblastoma and Immune Checkpoint Inhibitors: A Glance at Available Treatment Options and Future Directions.International journal of molecular sciences · 2024Review
- Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma.The Journal of clinical investigation · 2024Article
- ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.Cell · 2024Article
- Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.Nature communications · 2024Article
- Targeting ATR in patients with cancer.Nature reviews. Clinical oncology · 2024Review
- The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment.Nature communications · 2024Article
- Glioma-Immune Cell Crosstalk in Tumor Progression.Cancers · 2024Review
- PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.Cell reports. Medicine · 2023Article
- Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway.Journal for immunotherapy of cancer · 2023Article
- Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade.Nature communications · 2023Article
- Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment.The Journal of clinical investigation · 2023Review
- Leveraging the replication stress response to optimize cancer therapy.Nature reviews. Cancer · 2023Review
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Authors and funding
13 authors.
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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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