Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)–expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti–PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti–PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti–PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

中文翻译：

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ATR 介导的 CD47 和 PD-L1 上调限制了放疗诱导的结直肠癌免疫启动和远隔反应

结直肠癌 (CRC) 的放射治疗 (RT) 可以引发全身性的针对肿瘤相关抗原 (TAA) 表达的 CRC 细胞的适应性免疫。然而，远侧肿瘤缓解极为罕见，CRC 中的辐照后免疫逃逸机制仍然难以捉摸。在这里，我们发现照射后的 CRC 细胞使用 ATR 介导的 DNA 修复信号通路上调 CD47 和 PD-L1，它们分别通过 SIRPα 和 PD-1 的参与阻止抗原呈递细胞的吞噬作用，从而限制 TAA交叉呈递和先天免疫激活。这种辐照后 CD47 和 PD-L1 上调在各种人类实体瘤细胞中观察到。与此一致，对新辅助放疗反应不佳的直肠癌患者在照射后 CD47 水平显着升高。RT、抗 SIRPα 的组合，和抗 PD-1 逆转适应性免疫抗性并推动有效的 TAA 交叉呈递，导致强大的 TAA 特异性 CD8 T 细胞启动、T 效应器的功能激活以及 T 细胞克隆性和克隆多样性增加。我们观察到在三种不同的小鼠 CRC 模型（包括盲肠原位模型）中，放疗/抗 SIRPα/抗 PD-1 的完全缓解率显着提高，并且存活时间延长。三联疗法的疗效依赖于 STING，因为敲除动物失去了在 RT 中添加抗 SIRPα 和抗 PD-1 的大部分益处。尽管激活了整个髓样基质，但增强的树突细胞功能是 CD8 T 细胞启动的大部分改进。这些数据表明 ATR 介导的 CD47 和 PD-L1 上调是抑制辐射诱导的免疫启动的关键机制。RT 与 SIRPα 和 PD-1 阻断相结合可促进强大的抗肿瘤免疫启动，从而导致全身性肿瘤消退。