@article{2310cec7c8194a27b624b983887c1f1f,
title = "Chromatin regulator chd1 remodels the immunosuppressive tumor microenvironment in pten-deficient prostate cancer",
abstract = "Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identified CHD1 as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic under-standing of, the essential role of CHD1 in PTEN-deficient prostate cancer. In Pten and Pten/Smad4 genetically engineered mouse models, prostate-specific deletion of Chd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identified IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. Given the prominent role of MDSCs in suppressing responsiveness to immune checkpoint inhibitors (ICI), our genetic and tumor biological findings support combined testing of anti-IL6 and ICI therapies, specifically in PTEN-deficient prostate cancer. SIGNIFICANCE: We demonstrate a critical role of CHD1 in MDSC recruitment and discover CHD1/IL6 as a major regulator of the immunosuppressive TME of PTEN-deficient prostate cancer. Pharmacologic inhibition of IL6 in combination with immune checkpoint blockade elicits robust antitumor responses in prostate cancer.",
author = "Di Zhao and Li Cai and Xin Lu and Xin Liang and Jiexi Li and Peiwen Chen and Michael Ittmann and Xiaoying Shang and Shan Jiang and Haoyan Li and Chenling Meng and Ivonne Flores and Song, {Jian H.} and Horner, {James W.} and Zhengdao Lan and Wu, {Chang Jiun} and Jun Li and Qing Chang and Chen, {Ko Chien} and Guocan Wang and Pingna Deng and Spring, {Denise J.} and Wang, {Y. Alan} and Depinho, {Ronald A.}",
note = "Funding Information: The authors thank MD Anderson{\textquoteright}s Sequencing and Microarray Facility and Flow Cytometry and Cellular Imaging Core Facility, which are supported by an NCI Cancer Center Support Grant (P30 CA16672), and Baylor College of Medicine GEM Core. This work was supported in part by the Prostate Cancer Foundation Young Investigator Award 17YOUN18 (to D. Zhao), NIH Pathway to Independence Award-NCI 1K99CA226360 (to D. Zhao), CPRIT Recruitment of First-Time Tenure-Track Faculty Award RR190021 (to D. Zhao, a CPRIT Scholar in Cancer Research), PCF Challenge Award 17CHAL17 (to R.A. DePinho and Y.A. Wang), NIH 1R01CA231349-01A1 (to Y.A. Wang), and MDACC Prostate Cancer Moonshot (to R.A. DePinho). Funding Information: The authors thank MD Anderson?s Sequencing and Microarray Facility and Flow Cytometry and Cellular Imaging Core Facility, which are supported by an NCI Cancer Center Support Grant (P30 CA16672), and Baylor College of Medicine GEM Core. This work was supported in part by the Prostate Cancer Foundation Young Investigator Award 17YOUN18 (to D. Zhao), NIH Pathway to Independ-ence Award-NCI 1K99CA226360 (to D. Zhao), CPRIT Recruitment of First-Time Tenure-Track Faculty Award RR190021 (to D. Zhao, a CPRIT Scholar in Cancer Research), PCF Challenge Award 17CHAL17 (to R.A. DePinho and Y.A. Wang), NIH 1R01CA231349-01A1 (to Y.A. Wang), and MDACC Prostate Cancer Moonshot (to R.A. DePinho). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = sep,
doi = "10.1158/2159-8290.CD-19-1352",
language = "English (US)",
volume = "10",
pages = "1374--1387",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}
