Editors' ChoiceCancer

The two immune sides of obesity

See allHide authors and affiliations

Science Translational Medicine  28 Nov 2018:
Vol. 10, Issue 469, eaav9148
DOI: 10.1126/scitranslmed.aav9148


Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to immune checkpoint blockade.

Cancer immunotherapy is revolutionizing the clinical management of a variety of malignancies, arousing tremendous enthusiasm among clinicians, scientists, and patients. In particular, monoclonal antibodies targeting the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway have shown remarkable antitumor activity and have been approved for numerous tumor types. However, despite the unprecedented efficacy of these agents, the majority of the patients do not respond, highlighting the urgent need to identify reliable biomarkers. High tumor mutational burden and the presence of immune cells in the tumor microenvironment correlate with better responses to anti–PD-1 therapies. However, the role of other factors, such as age or body mass index (BMI) is not well established. In a recent study, Wang et al. have found that obesity impairs T cell function but at the same time improves response to anti–PD-1 therapy.

Obesity, which is defined by a BMI higher than 30, is a major risk factor for several chronic diseases, including diabetes and cancer. At the molecular level, obesity is associated with an increased production of proinflammatory cytokines, insulin, fatty acids, and leptin, which favor tumor initiation and progression. Although the causal role of obesity in promoting tumor initiation and progression is well established, the effects of obesity on antitumor immunity and response to immunotherapy are less understood. In this study, the authors investigated the effect of obesity on T cell function and found that obesity was associated with T cell dysfunction, characterized by increased expression of PD-1 in mice, nonhuman primates, and humans. In addition, obesity resulted in impaired antitumor immunity and subsequently increased growth of melanoma, lung, and breast tumors in mice. Mechanistically, leptin, a hormone that inhibits hunger and is overproduced in obesity, was shown to enhance the expression of PD-1 by T cells, causally linking obesity with T cell dysfunction. Last, the authors exploited the obesity-induced T cell dysfunction for cancer treatment with anti–PD-1 antibodies, observing improved responses of melanomas and lung tumors in obese mice and patients. Although these findings need to be confirmed in a broader spectrum of tumor types, they demonstrate how a negative effect of obesity creates a vulnerability that can be harnessed for cancer treatment.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article