Innate Immune Mechanisms Contributing to Cancer Growth in Obesity

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Supplement Project Summary Obesity (body mass index ≥30 kg/m2), which affects at least one-third of the U.S. population, is more prevalent among African American and Hispanic populations and increases the risks of both developing and dying from certain cancers. However, the cellular and molecular mechanisms underlying these risks are unknown. Our studies demonstrate that colorectal cancer (CRC) and other tumors grow considerably faster in diet-induced obese mice due to the immunosuppressive actions of the acid-sensing receptor, G-protein coupled 65 (GPR65), on tumor-associated macrophages (TAMs). In the parent project, we are analyzing the intracellular signals from GPR65 that alter TAM function and tumor growth in obese mice, identifying the mechanism by which a high-fat diet (HFD) promotes GPR65 signaling in TAMs, and assessing the effects of targeting GPR65 for tumor immunotherapy in obese and non-obese mice. Data from the parent project indicate that altered lipid metabolism is responsible for upregulating GPR65 expression on TAMs in the tumors of obese mice. Since the lipid profile in tumors of obese humans is nearly identical to that of tumors from obese mice, we believe there is a high likelihood that tumors from obese humans will display a similar immune profile. In the proposed supplement project, we will extend our studies to human cancers including CRC, hepatocellular carcinoma (HCC), pancreatic adenocarcinoma (PDAC) and breast carcinomas in order to test the hypothesis that GPR65 expression on TAMs is associated with obesity, altered TAM function and alterations of other immune cells in the tumor microenvironment. We further hypothesize that these effects of obesity on immune cells in cancer are equivalent in African American, Hispanic, Asian and non-Hispanic White populations and not determined on the basis of race or ethnicity. To analyze the tumors, we will use mass cytometry (CyTOF) to examine the frequencies, surface, and cytokine profiles of immune cells in the tumor, use single cell RNA sequencing (scRNA seq) to analyze the functional profiles of these cells and use CODEX to analyze the spatial relationships between TAMs and other immune cells. We will then compare the results between tumors from patients of different racial and ethnic backgrounds. The results of these experiments are expected to confirm both of our hypotheses and provide a strong rationale for future studies in which these hypotheses are tested in larger populations, and novel therapies targeting GPR65 are developed and evaluated in clinical trials.