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

Autor: Ban Y; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA., Markowitz GJ; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA., Zou Y; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA., Ramchandani D; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA., Kraynak J; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Sheng J; Systems Medicine and Bioengineering Department and Bioinformatics and Biostatistics Cores, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA., Lee SB; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA., Wong STC; Systems Medicine and Bioengineering Department and Bioinformatics and Biostatistics Cores, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA., Altorki NK; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. nkaltork@med.cornell.edu.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. nkaltork@med.cornell.edu.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. nkaltork@med.cornell.edu.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. nkaltork@med.cornell.edu., Gao D; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. dig2009@med.cornell.edu.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. dig2009@med.cornell.edu.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. dig2009@med.cornell.edu.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. dig2009@med.cornell.edu., Mittal V; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu.; Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2021 Sep; Vol. 2 (9), pp. 919-931. Date of Electronic Publication: 2021 Sep 20.
DOI: 10.1038/s43018-021-00245-1
Abstrakt: Radiation therapy (RT) in combination with 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 ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, 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 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC.
Competing Interests: Competing financial interests: The authors declare no competing financial interests. The authors declare no potential conflicts of interest
Databáze: MEDLINE
Externí odkaz: