Split immunomodulatory impact of leptin on human myeloid cells: key role of IDO1 in counteracting the immunostimulatory effect of leptin

Abstract

Abstract Obesity increases cancer incidence and aggressiveness but is paradoxically associated with improved response to immunotherapy. Here, we show that intratumoral levels of leptin (LEP), a factor contributing to the development of obesity, predict improved outcomes of breast and liver cancers. In contrast, these levels of LEP are associated with poor survival of patients with colon and esophageal cancers, where they are uniquely correlated with high IDO1 levels in tumor-associated myeloid cells. LEP-exposed human macrophages show elevated levels of multiple T cell–activating factors but also show NF-κB– and STAT3-dependent IDO1 induction, which synergize with IFN-γ in activating the kynurenine pathway, resulting in their T cell–suppressive function. IDO1 inhibition reprograms the LEP-exposed macrophages from metabolic suppression to enhanced T cell–stimulatory function. The double-edged impact of LEP on human myeloid cells helps explain obesity-associated immune dysfunction and the “obesity paradox,” suggesting that IDO1 inhibition may be selectively beneficial in patients who have obesity and cancer with high levels of LEP.