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 chromodomain-helicase-DNA-binding protein 1 (CHD1) as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic understanding 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 remodeling characterized by reduced MDSCs and increased CD8+ T cells. Further analysis identified IL-6 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-IL-6 and ICI therapies, specifically in PTEN-deficient prostate cancer.