Radiation-activated secretory proteins of Scgb1a1 ⁺ club cells increase the efficacy of immune checkpoint blockade in lung cancer

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.