Macrophage repolarization via leptin increases immunotherapy efficacy in obesity

Abstract

Abstract Immune checkpoint blockade treatment is life-saving for some patients, but most do not respond. While systemic immune dysfunction occurs in obesity, early studies have surprisingly shown that obesity increases immunotherapy efficacy. Obesity promotes immune dysfunction through T cell exhaustion, which is well understood, but obesity also affects macrophage polarization, which is understudied in the setting of obesity, cancer, and immunotherapy. Male C57BL/6 mice received a 60 kcal high-fat diet for 12 weeks and received 250,000 MC38 colon cancer cells subcutaneously. Mice received 200 ug of IgG control antibody or anti-PD-1 antibody every 2 days starting on day 5. Tumors were collected 16 days post-injection and processed for flow cytometry. Samples were stained for T cells (CD4+ helper, T Regulatory, and CD8+ cells), macrophages (M1 and M2), and myeloid derived suppressor cells. Obese mice had larger tumor growth rates and tumor burden than lean mice. Tumors in obese mice had fewer CD8+ and CD4+ T cells, but the T cells expressed higher levels of CD44 and PD1. MC38 tumors in obese mice had greater immunotherapy efficacy than lean mouse tumors. Flow cytometry revealed that the anti-PD-1 treatment repolarized the macrophages to an M1-phentoype, whereas anti-PD-1 treatment in lean mice increased the T cell percentage in tumors. In experiments where lean mice received leptin treatments to emulate the elevated leptin in obesity, leptin-treated mice had smaller tumors and an increased M1-phenotype of macrophage. Our work shows that macrophage repolarization was the most significant immune cell change in our obesity and immunotherapy studies. Future work will investigate the efficacy of immunotherapy in macrophage depleted models.