Abstract 2121: Gene expression and functional characterization of obesity-induced MDSC to uncover the link between obesity and cancer risk

Abstract

Abstract Strong epidemiologic evidence suggests that excess body weight gain is a major risk of at least 13 different types of cancers. One of the mechanisms explaining the increased cancer incidence in obese patients is associated with the chronic low-grade inflammatory condition. Myeloid cells including macrophages and Myeloid-derived suppressor cells (MDSC) are increased in advanced adiposity. Previous studies in mouse models have shown that obesity-induced MDSC play a protective role on metabolic control; however, in the presence of malignant cells, MDSC facilitates tumor growth and metastasis. Our data show that compared to non-obese individuals, patients with severe obesity (body mass index [BMI] > 40) have a significant increase of circulating granulocytic cells displaying a gene signature resembling tumor-MDSC. Intriguingly, obesity-induced MDSC lacked the potent immunosuppressive function; and therefore, we called them obesity-induced G-MDSC-like cells (Ob-MDSC). The mechanisms underlying the regulation of MDSC phenotype in obesity and obesity-related cancer are unclear. We found that LDL, one altered obesity-related factor, and LPS differentially impact the expression of several genes including the immunosuppressive MDSC markers, arginase-1 and iNOS, when comparing mouse bone marrow-derived MDSC from high-fat fed mice with low-fat fed mice. This finding indicates that the responsiveness of MDSC may be regulated by their long-lasting exposure to the obese microenvironment. Therefore, we propose that long-term adaptation of MDSC is induced by dysfunctional metabolic factors in obesity that modulate their response to subsequent triggers, such as signals derived by the tumor microenvironment (TMA) in the context of obesity-associated cancer. Our data from obese mice with Diethylnitrosamine (DEN)-induced hepatocellular carcinoma and genetically altered hepatic lipid and lipoprotein metabolism show an increased infiltration of G-MDSC associated with enhanced tissue chemokine signaling pathway, ECM remodeling/metastasis, inflammation, and epigenetic and transcriptional regulation. Together our data suggest that chronic exposure to an obesity-related environment establishes a phenotype prone to become pro-tumor MDSC. The identification of key regulators of the gene expression driving the immunosuppressive phenotype of MDSC in obesity is critical for the discovery of therapeutical targets to reduce the risk of obesity-associated cancers. Citation Format: Maria D. Sanchez-Pino, Ramesh Thylur Puttalingaiah, Jone Garai, Jovanny Zabaleta, Randall L. Mynatt, William Richardson, Augusto Ochoa. Gene expression and functional characterization of obesity-induced MDSC to uncover the link between obesity and cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2121.