Thiazolidinedione enhances the efficacy of immunotherapy in murine melanoma

Am J Physiol Endocrinol Metab. 2024 Jan 31. doi: 10.1152/ajpendo.00346.2023. Online ahead of print.ABSTRACTSeveral clinical studies observed a surprising beneficial effect of obesity to increase immunotherapy responsiveness in melanoma patients, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug used to treat diabetes by sequestering fatty acids in the metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-Programmed Cell Death Protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, a murine melanoma model that is initially sensitive to immunotherapy. We observed a transition from high to intermediate PD-1 expression in tumor-infiltrating CD8+ T cells. Moreover, we observed inhibited PD-1 expression in mouse and human T cells treated with TZD in vitro. In addition to its direct impact on immune cells, TZD also decreases circulating insulin concentrations, while insulin induced exhaustion in T cell culture. In TZD-treated mice, we observed higher fatty acid concentrations in the tumor microenvironment, with fatty acids protecting against exhaustion in culture. Together, these data are consistent with an indirect mechanism of TZD inhibiting T cell exhaustion. Finally, we analyzed imaging data from melanoma patients before and after anti-PD-1 treatment and confirmed a beneficial effect of increased subcutaneous fat on anti-PD-1 r...
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Source Type: research