Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

By Ziming Wang, Ethan G. Aguilar, Jesus I. Luna, C. Dunai, Lam T. Khuat, Catherine T. Le, Annie Mirsoian, Christine M Minnar, Kevin M. Stoffel, Ian R. Sturgill and 23 more. Nature Medicine, 2018

762 citations recorded by the source corpus.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity. Obesity promotes tumor growth yet simultaneously increases susceptibility to PD-1-targeted cancer immunotherapy.

Subfields: Epidemiology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/d37c9a066871128026dcc9d4b67554f394c179db

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Citations in the corpus

• Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “Because both TMB (40) and BMI (44) have been previously linked to ICB responses, our findings highlight the importance of TFH-related cell populations in the antitumor response.”
• Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity (2020, background): “Finally, a recent study found that diet-induced obesity enhances responses to PD-1/PD-L1 therapy in the B16 mouse melanoma model (Wang et al., 2019), which matches clinical data showing better outcomes for obese melanoma patients treated with immune checkpoint blockade (Cortellini et al.”