Leptin Augments Anti-Tumor Immunity in Obesity by Repolarizing Tumor-Associated Macrophages

While obesity can promote cancer, it may also increase immunotherapy efficacy in what has been termed the obesity-immunotherapy paradox. Mechanisms of this effect are unclear, although obesity alters key inflammatory cytokines and can promote an inflammatory state that may modify tumor infiltrating lymphocytes (TIL) and tumor associated macrophage (TAM) populations. To identify mechanisms by which obesity affects anti-tumor immunity, we examined changes in cell populations and the role of the pro-inflammatory adipokine leptin in immunotherapy. Single cell RNAseq revealed that obesity decreased TIL frequencies and flow cytometery confirmed altered macrophage phenotypes with lower expression of iNOS and MHCII in tumors of obese animals. When treated with anti-PD-1 antibodies, however, obese mice had a greater absolute decrease in tumor burden than lean mice and a repolarization of the macrophages to inflammatory M1-like phentoypes. Mechanistically, leptin is a pro-inflammatory adipokine that is induced in obesity and may mediate enhanced anti-tumor immunity in obesity. To directly test the effect of leptin on tumor growth and anti-tumor immunity, lean mice were treated with leptin and tumors were observed over time. Treatment with leptin, acute or chronic, was sufficient to enhance anti-tumor efficacy similar to anti-PD-1 checkpoint therapy. Further, leptin and anti-PD-1 co-treatment may enhance anti-tumor effects consistent with an increase in M1-like TAM frequency compared to non-leptin treated mice. These data demonstrate that obesity has dual effects in cancer through promotion of tumor growth while simultaneously enhancing anti-tumor immunity through leptin-mediated macrophage reprogramming.