ATR 抑制剂增强了对 DNA 复制叉口的化学治疗药物杀伤肿瘤细胞，但也会杀伤快速增殖的免疫细胞，包括活化的 T 细胞。然而，ATR 抑制剂 (ATRi) 和放疗 (RT) 可以结合起来在小鼠模型中产生 CD8+ T 细胞依赖性的抗肿瘤反应。为了确定 ATRi 和 RT 的最佳安排方案，我们确定了 AZD6738 (ATRi) 短程与长期日常治疗对 RT (第 1-2 天) 反应的影响。短期 ATRi (第 1-3 天) 加上 RT 导致肿瘤引流淋巴结 (DLN) 中的特异性抗原效应 CD8+ T 细胞的扩增，在 RT 1 周后出现。这是通过肿瘤浸润和外周 T 细胞的急性减少以及 ATRi 停止后快速增殖反弹，肿瘤中炎性信号的增加 (IFN-β，趋化因子，尤其是 CXCL10) 和 DLN 的炎性细胞的积累所先导的。相反，长期 ATRi (第 1-9 天) 阻止了 DLN 中特定于肿瘤抗原的效应 CD8+ T 细胞的扩增，并完全废除了短程 ATRi 与 RT 和抗 PD-L1 的治疗效果。我们的数据表明，ATRi 停止对于允许 CD8+ T 细胞对 RT 和免疫检查点抑制剂作出反应至关重要。

Inhibitors of the DNA damage signaling kinase ATR increase tumor cell killing by chemotherapies that target DNA replication forks but also kill rapidly proliferating immune cells including activated T cells. Nevertheless, ATR inhibitor (ATRi) and radiotherapy (RT) can be combined to generate CD8+ T cell-dependent antitumor responses in mouse models. To determine the optimal schedule of ATRi and RT, we determined the impact of short-course versus prolonged daily treatment with AZD6738 (ATRi) on responses to RT (days 1-2). Short-course ATRi (days 1-3) plus RT caused expansion of tumor antigen-specific, effector CD8+ T cells in the tumor-draining lymph node (DLN) at 1 week after RT. This was preceded by acute decreases in proliferating tumor-infiltrating and peripheral T cells and a rapid proliferative rebound after ATRi cessation, increased inflammatory signaling (IFN-β, chemokines, particularly CXCL10) in tumors, and an accumulation of inflammatory cells in the DLN. In contrast, prolonged ATRi (days 1-9) prevented the expansion of tumor antigen-specific, effector CD8+ T cells in the DLN, and entirely abolished the therapeutic benefit of short-course ATRi with RT and anti-PD-L1. Our data argue that ATRi cessation is essential to allow CD8+ T cell responses to both RT and immune checkpoint inhibitors.