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.

中文翻译：

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复制应激反应缺陷与非高突变癌症对免疫检查点阻断的反应有关

免疫检查点阻断 (ICB) 治疗已对一部分癌症患者产生持久反应，ICB 反应的预测性生物标志物最初主要在高突变癌症的背景下确定。尽管最近的临床数据已证明某些非高突变癌症患者对 ICB 的临床反应，但先前建立的 ICB 反应生物标志物未能准确识别这些患者中的哪些可能受益于 ICB。在这里，我们证明了复制应激反应 (RSR) 缺陷基因表达特征，但与其他提议的生物标志物无关，与 12 个独立队列中的 ICB 反应相关，这些患者包括 7 种肿瘤类型的非高突变癌症患者，包括乳腺、前列腺、肾、脑。RSR 缺陷的诱导或抑制足以在乳腺癌和肾癌的临床前模型中调节对 ICB 的反应。从机制上讲，我们发现尽管在 RSR 缺陷型癌细胞中检查点激酶 1 信号通路被强烈激活，但异常的复制起点激发会导致复制蛋白 A 耗尽，从而导致免疫刺激性细胞溶质 DNA 的积累。我们进一步发现，在小鼠癌症模型和人类肿瘤中，缺乏 RSR 与增加的肿瘤内树突状细胞相吻合。总之，这项工作表明，RSR 缺陷基因特征可以准确地识别可能从多种非高突变肿瘤类型中受益的 ICB 患者，并且 RSR 缺陷的药理学诱导可能进一步扩大 ICB 对更多患者的益处。