Leptin regulates tryptophan metabolism of myeloid cells within the tumor microenvironment 3252

Description Obesity is a major risk factor for the incidence and severity of multiple cancer types. Growing body of evidence indicates that obesity is associated with dysregulated metabolism and immunity. Leptin, a hormone regulating hunger and energy balance, plays a key role in the development of obesity and systemic metabolic dysregulation. Leptin has been identified as an inducer of chronic inflammation promoting tumor growth, but the mechanism of its action and its function in modulating tumor microenvironment (TME) is poorly understood. Here, we demonstrate that leptin contributes to obesity-associated tumor-promoting status through dysregulation of tryptophan metabolism in TME of colorectal cancer. Analysis of colorectal cancer samples revealed that leptin expression was associated with high expression of enzymes involved in tryptophan metabolism, including IDO1. Using imaging mass cytometry, we observed that IDO1 was preferentially expressed by myeloid components within TME and was upregulated by exogenous leptin. Using human monocyte-derived macrophages as a model, we found that leptin mediated long-term upregulation of IDO1 through STAT3 and NF-κB pathways. Leptin-treated macrophages showed elevated secretion of tryptophan metabolites including kynurenine, which suppressed T cell responses. Our findings help to better understand the mechanism of obesity-associated immune dysfunction and design new therapeutic modalities. Funding Sources Supported by NIH/NCI grant P01CA234212, DOD grant W81XWH-19-1-0674, Jacobs Family Foundation and Roswell Park Institutional Funds. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)