Abstract B105: The impact of cholesterol and its metabolites on ovarian tumor microenvironment and cancer progression

Abstract

Ovarian cancer continues to have a high mortality and recurrence rate. Hence, there is an urgent need to develop new therapeutic or lifestyle strategies. In this regard, epidemiologic studies have implicated elevated cholesterol as a negative prognostic factor. Conversely, ovarian cancer patients prescribed cholesterol-lowering drugs (HMGCoA-R inhibitors; statins) exhibit significantly increased progression-free survival (PFS). In a cohort of 134 patients, we found high LDL cholesterol (≥130 mg/dL) is also associated with high tumor grade at diagnosis. Therefore, cholesterol appears to be clinically important for the progression of ovarian cancer. These observations highlight the potential relevance of previous work implicating the cholesterol metabolite, 27-hydroxychoelsterol (27HC), as a ligand for the estrogen and liver x receptors, providing a putative mechanism for the actions of cholesterol. CYP27A1 encodes the first enzyme in the alternative pathway of cholesterol catabolism, producing 27HC. Analysis of TCGA and other publicly available databases indicated that low CYP27A1 expression was associated with increased PFS. Conversely, high CYP7B1 expression, the enzyme that metabolizes 27HC, was associated with increased PFS. Therefore, we hypothesized that CYP27A1 is involved in ovarian cancer pathophysiology via 27HC signaling. To directly investigate the role of CYP27A1 in ovarian cancer progression, we monitored the growth of tumors grafted into the ovarian bursa area of wild-type and CYP27A1 knockout (KO) mice. Strikingly, we found that ovarian tumors failed to thrive in CYP27A1 KO mice, eventually completely regressing. Treatment with exogenous 27HC was able to sustain tumor growth in CYP27A1 KO mice, indicating that it was indeed a deficiency in 27HC that was mediating the antitumor effects in these mice. Somewhat paradoxically, we found 27HC had growth inhibitory effects on in vitro proliferation of ovarian cancer cells. However, analysis of tumors indicated that 27HC treatment was associated with the enrichment of certain myeloid populations, especially M-MDSCs. M-MDSCs are a myeloid-immune cell type known to be protumorigenic, at least in part through their suppression of cytotoxic CD8+ T cells. This would suggest that inhibition of CYP27A1 might improve the efficacy of immune checkpoint inhibition. Therefore, we tested the therapeutic utility of combining a small-molecule inhibitor of CYP27A1 with anti-PD-L1. Indeed, combining these two approaches significantly decreased ovarian tumor growth in a preclinical model. Collectively, our preliminary data indicate that cholesterol/27HC-axis modulates myeloid cells within tumor microenvironment and promotes cancer progression, revealing a novel therapeutic target for ovarian cancer treatments. Supported by NIH NCI R00CA172357 (E.R.N.), NIH NCI R01CA234025 (E.R.N.), a Cancer Scholars for Translational and Applied Research (C*STAR) Award (S.H.) and NIH T32EB019944 (S.H.). Citation Format: Sisi He, Liqian Ma, Georgina Cheng, Betsy Barnick, Marta Spain, Ronald Kimball, Amy E. Baek, Joanna Burdette, Erik R. Nelson. The impact of cholesterol and its metabolites on ovarian tumor microenvironment and cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B105.