Leptin Repolarizes Tumor-Associated Macrophages to Boost Immunotherapy Efficacy in Obesity
Dudzinski, Stephanie Odette
Immunotherapy is life-saving for some cancer patients and while obesity can promote cancer, it may also increase immunotherapy efficacy. Mechanisms of this effect have been unclear, although obesity can promote an inflammatory state that may modify tumor infiltrating lymphocytes and tumor associated macrophage (TAM) populations in tumors. To identify mechanisms by which obesity affects anti-tumor immunity, diet-induced obese and lean mice received subcutaneous MC38-CEA1 colon cancer tumors. Obesity increased tumor growth rate and tumor burden. Fewer immune cells were present in tumors from obese mice, and the T cells had an activated and exhausted phenotype. Macrophages in obese animals had decreased expression of iNOS2 and MHCII, supporting a weaker “M1” anti-tumor phenotype compared to lean mice. When treated with anti-PD-1 antibodies, however, obese mice had a greater absolute decrease in tumor burden than lean mice. PD-1 blockade repolarized the macrophages to an M1-phentoype in obese mice but this did not occur in the lean mice. Mechanistically, leptin is a pro-inflammatory adipokine that is increased in obesity and may mediate enhanced anti-tumor immunity in obesity. To test the effect of leptin on tumor growth and anti-tumor immunity, lean mice were treated with leptin and tumors were observed over time. Leptin had single-agent preventative and therapeutic anti-tumor efficacy similar to PD-1 checkpoint therapy. These data demonstrate that obesity has dual effects in cancer through promotion of tumor cell initiation while also enhancing anti-tumor immunity through elevated levels of leptin that can reprogram inflammatory macrophages.