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

Wang, Ziming, Aguilar, Ethan G, Luna, Jesus I, Dunai, Cordelia, Khuat, Lam T, Le, Catherine T, Mirsoian, Annie, Minnar, Christine M, Stoffel, Kevin M, Sturgill, Ian R, Grossenbacher, Steven K, Withers, Sita S, Rebhun, Robert B, Hartigan-O'Connor, Dennis J, Méndez-Lagares, Gema, Tarantal, Alice F, Isseroff, R Rivkah, Griffith, Thomas S, Schalper, Kurt A, Merleev, Alexander, Saha, Asim, Maverakis, Emanual, Kelly, Karen, Aljumaily, Raid, Ibrahimi, Sami, Mukherjee, Sarbajit, Machiorlatti, Michael, Vesely, Sara K, Longo, Dan L, Blazar, Bruce R, Canter, Robert J, Murphy, William J and Monjazeb, Arta M (2019) Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine, 25 (1), 141-151. (doi:10.1038/s41591-018-0221-5).

Abstract

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.

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