Ban et al. demonstrated that the secretome of radiation therapy (RT)-induced lung-resident Scgb1a1+ club cells enhanced the therapeutic efficacy of ICIs in NSCLC. In the lung HKP1 tumor model, 4 Gy-RT increased the proliferation of club cells and their secretory proteins, which increased cytotoxic CD8+ T cell infiltration, reduced suppressive functions of MDSCs, and improved the efficacy of PD-1 blockade in a club cell-dependent manner. In a phase II neoadjuvant NSCLC clinical trial, RT increased club cell-secreted CC10 levels in patients who responded to neoadjuvant RT + ICI. Administration of protein “club cocktail” enhanced the efficacy of anti-PD-1 therapy in vivo.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. (2) Department of Cell and Developmental Biology, Weill Cornell
Medicine, New York, NY, USA. (3
Author Info: (1) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. (2) Department of Cell and Developmental Biology, Weill Cornell
Medicine, New York, NY, USA. (3) Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Radiology, Weill
Cornell Medicine, New York, NY, USA. (5) Systems Medicine and Bioengineering Department and Bioinformatics and Biostatistics Cores, Houston Methodist
Cancer Center, Houston Methodist Hospital, Houston, TX, USA. 6Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
nkaltork@med.cornell.edu; dig2009@med.cornell.edu; vim2010@med.cornell.edu.
