Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer

Abstract

Genetic inactivation of <i>PTEN</i> is common in prostate cancer and correlates with poorer prognosis. We previously identified <i>CHD1</i> as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive <i>in vivo</i> genetic evidence for, and mechanistic understanding of, the essential role of CHD1 in PTEN-deficient prostate cancer. In <i>Pten</i> and <i>Pten</i>/<i>Smad4</i> genetically engineered mouse models, prostate-specific deletion of <i>Chd1</i> resulted in markedly delayed tumor progression and prolonged survival. <i>Chd1</i> 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.<i>This article is highlighted in the In This Issue feature, p. 1241</i>.