@article{892c8e61361547648761e3f00f3e0f96,
title = "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 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 = "Yi Ban and Markowitz, {Geoffrey J.} and Yue Zou and Divya Ramchandani and Jeffrey Kraynak and Jianting Sheng and Lee, {Sharrell B.} and Wong, {Stephen T.C.} and Altorki, {Nasser K.} and Dingcheng Gao and Vivek Mittal",
note = "Funding Information: We thank J. Xiang of the Genomics Resources Core Facility and J. McCormick of the Flow Cytometry Core Facility for their professional advice. We thank the Formenti and Demaria labs for providing expertise and guidance on the use of focal tumor radiation. The small animal irradiator was obtained with the support of NIH S10 RR027619-01. We thank C. Spinelli, J. Gakuria, A. Nasar and M. Malbari for clinical data support. We also thank X. Lin of Rutgers University for statistical consultation. This work was supported in part by National Cancer Institute grant National Institutes of Health (NIH) U01 CA188388 (V.M. and S.T.W.), 1UG3 CA244697 (V.M and N.K.A). Y.B. was supported by NIH R01 CA244413. G.J.M. was supported by postdoctoral fellowships of National Cancer Institute T32 CA203702, NIH CTSC KL2-TR-002385 and PhRMA Foundation 2020 Postdoctoral fellowship in Translational Medicine. This work was also supported by funds from The Neuberger Berman Foundation Lung Cancer Research Center; a generous gift from Jay and Vicky Furman; and generous funds donated by patients in the Division of Thoracic Surgery to N.K.A. The funding organizations played no role in experimental design, data analysis or manuscript preparation. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = sep,
doi = "10.1038/s43018-021-00245-1",
language = "English (US)",
volume = "2",
pages = "919--931",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "9",
}