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

Ziming Wang, Ethan G. Aguilar, Jesus I. Luna, Cordelia Dunai, Lam T. Khuat, Catherine T. Le, Annie Mirsoian, Christine M. Minnar, Kevin M. Stoffel, Ian R. Sturgill, Steven K. Grossenbacher, Sita S. Withers, Robert B. Rebhun, Dennis J. Hartigan-O’Connor, Gema Méndez-Lagares, Alice F. Tarantal, R. Rivkah Isseroff, Thomas S. Griffith, Kurt A. Schalper, Alexander MerleevAsim Saha, Emanual Maverakis, Karen Kelly, Raid Aljumaily, Sami Ibrahimi, Sarbajit Mukherjee, Michael Machiorlatti, Sara K. Vesely, Dan L. Longo, Bruce R. Blazar, Robert J. Canter, William J. Murphy, Arta M. Monjazeb

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)141-151
Number of pages11
JournalNature Medicine
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Funding Information:
We would like to thank W. Ma and M. Metcalf from the Murphy lab, D. Rowland, A. Chaudhari and Z. Harmany from the UC Davis CMGI and J. Chen in the UC Davis Pathology Core for their technical expertise and help. We would also like to thank the other members in the Murphy lab for providing feedback and suggestions during preparation of the manuscript. This was work funded by NIH grant R01 CA095572, R01 CA195904, R01 CA214048, P01 CA065493, R01 HL085794, the California National Primate Research Center base operating grant (OD011107), the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373) and the UC Davis Mouse Metabolic Phenotyping Center (MMPC) grant (DK092993). The content of this publication does not necessarily reflect the view or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, NCI, NHLBI and Center for Cancer Research.

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

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