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 Merleev & 13 others Asim 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 journalArticle

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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

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T-cells
Tumors
Obesity
T-Lymphocytes
Neoplasms
Immunotherapy
Bearings (structural)
Oncology
Tumor Biomarkers
Leptin
Aging of materials
Pandemics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Wang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., ... Monjazeb, A. M. (2019). Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine, 25(1), 141-151. https://doi.org/10.1038/s41591-018-0221-5

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.; Monjazeb, Arta M.

In: Nature Medicine, Vol. 25, No. 1, 01.01.2019, p. 141-151.

Research output: Contribution to journalArticle

Wang, Z, Aguilar, EG, Luna, JI, Dunai, C, Khuat, LT, Le, CT, Mirsoian, A, Minnar, CM, Stoffel, KM, Sturgill, IR, Grossenbacher, SK, Withers, SS, Rebhun, RB, Hartigan-O’Connor, DJ, Méndez-Lagares, G, Tarantal, AF, Isseroff, RR, Griffith, TS, Schalper, KA, Merleev, A, Saha, A, Maverakis, E, Kelly, K, Aljumaily, R, Ibrahimi, S, Mukherjee, S, Machiorlatti, M, Vesely, SK, Longo, DL, Blazar, BR, Canter, RJ, Murphy, WJ & Monjazeb, AM 2019, 'Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade', Nature Medicine, vol. 25, no. 1, pp. 141-151. https://doi.org/10.1038/s41591-018-0221-5
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. ; Monjazeb, Arta M. / Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. In: Nature Medicine. 2019 ; Vol. 25, No. 1. pp. 141-151.
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