Radiation therapy (RT) in combination with an immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC); however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICIs. The immune-modulating functions of RT were ascribed to activated lung-resident Scgb1a1⁺ club cells. Notably, mice with club-cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified eight club cell secretory proteins that inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation and enhanced antitumor immunity. Notably, CC10, a member of club cell secretome, was increased in plasma of patients with NSCLC responding to the combination therapy. By revealing an immunoregulatory role of club cells, our studies have the potential to guide future clinical trials of ICIs in NSCLC.

放射治疗 (RT) 与免疫检查点抑制剂 (ICI) 联合代表了治疗非小细胞肺癌 (NSCLC) 的有希望的治疗方案；然而，潜在的机制没有得到很好的表征。我们确定了特定剂量的放疗，当与 ICI 联合使用时，该放疗可在 NSCLC 模型中实现肿瘤消退并提高生存率。RT 的免疫调节功能归因于激活的肺驻留Scgb1a1 ⁺俱乐部细胞。值得注意的是，具有突触体相关蛋白 23 的俱乐部细胞特异性敲除的小鼠未能从联合治疗中受益，这表明俱乐部细胞分泌组的关键作用。我们鉴定了八种俱乐部细胞分泌蛋白，它们抑制免疫抑制性骨髓细胞，减少促肿瘤炎症并增强抗肿瘤免疫力。值得注意的是，对联合治疗有反应的 NSCLC 患者的血浆中，CC10 是俱乐部细胞分泌组的成员之一。通过揭示俱乐部细胞的免疫调节作用，我们的研究有可能指导未来 ICI 在 NSCLC 中的临床试验。