Purpose: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. Experimental Design: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. Results: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. Conclusions: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

中文翻译：

---

靶向树突状细胞分泌的免疫调节细胞因子 CCL22 可减轻放射抗性

目的：辐射介导的免疫抑制限制了疗效，并且是癌症治疗的障碍。辐射会诱导肿瘤免疫的负调节因子，包括调节性 T 细胞 (Treg)。放疗 (RT) 后 Treg 浸润的机制尚不清楚。鉴于树突状细胞 (cDC) 维持 Treg，我们试图识别和靶向 cDC 信号传导以阻止放疗后 Treg 浸润。实验设计：转录组学和高维流式细胞术揭示了小鼠肿瘤 cDC 的变化，这些变化不仅介导 RT 后 Treg 浸润，而且与人类癌症数据集中较差的生存率相关。在同基因小鼠肿瘤中测试了干扰 cDC-CCL22-Treg 轴的抗体。研究人员检查了原型干扰素-抗表皮生长因子受体融合蛋白 (αEGFR-IFNα)，以阻止 Treg 浸润并促进 RT 后 CD8+ T 细胞反应。结果：辐射扩大了富含免疫调节标记的成熟 cDC1 群体，这些标记通过 Treg 招募趋化因子 CCL22 介导 Treg 浸润。阻断 CCL22 或 Treg 消耗均可增强 RT 疗效。 αEGFR-IFNα 阻断 cDC1 CCL22 的产生，同时诱导抗肿瘤 CD8+ T 细胞反应，以增强多种表达 EGFR 的小鼠肿瘤模型中的 RT 疗效，包括全身给药后。结论：我们发现了一种以前未被认识到的 cDC 机制，它介导放疗后 Treg 肿瘤浸润。我们的研究结果表明阻断 cDC1-CCL22-Treg 轴可增强 RT 疗效。添加到 RT 中的 αEGFR-IFNα 提供了比全身性游离干扰素给药更好的强大抗肿瘤反应，并且可以克服干扰素治疗的临床限制。我们的研究结果强调了放疗后 cDC 的复杂行为，并为克服放疗驱动的免疫抑制以提高放疗疗效提供了新的治疗策略。