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


ABSTRACT: 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.

SUBMITTER: Ban Y 

PROVIDER: S-EPMC8670735 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Ban Yi Y   Markowitz Geoffrey J GJ   Zou Yue Y   Ramchandani Divya D   Kraynak Jeffrey J   Sheng Jianting J   Lee Sharrell B SB   Wong Stephen T C STC   Altorki Nasser K NK   Gao Dingcheng D   Mittal Vivek V  

Nature cancer 20210920 9


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 synaptos  ...[more]

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