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Cited by 865Cancer Immunotherapy and BiomarkersImmune cells in cancerT-cell and B-cell Immunology

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

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Wang, Ziming, Aguilar, Ethan G., Luna, Jesus I., Dunai, Cordelia, Khuat, Lam T., Le, Catherine T., Mirsoian, Annie, Minnar, Christine M. +25 more·2019·Nature Medicine
DOI 10.1038/s41591-018-0221-5PMC PMC6324991
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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.

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  • The importance of the leptin/STAT3 pathway in immune aging, tumor progression, and T cell dysfunction in cancer is suggested by findings that obese cancer patients respond better than nonobese patients to checkpoint therapy, especially PD1/PD-L1 therapy, perhaps due to increased leptin signaling.

    “The importance of the leptin/STAT3 pathway in immune aging, tumor progression, and T cell dysfunction in cancer is suggested by recent findings that obese cancer patients respond better than nonobese patients to checkpoint therapy, especially therapy directed against the programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) axis perhaps due to increased leptin signaling”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Wang et al., 2019

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Cited by

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Authors
Wang, Z., Aguilar, E. G., Luna, J. I., Dunai, C., Khuat, L. T., Le, C. T., Mirsoian, A., Minnar, C. M., Stoffel, K. M., Sturgill, I. R., Grossenbacher, S. K., Withers, S. S., Rebhun, R. B., Hartigan-O’Connor, D. J., Méndez-Lagares, G., Tarantal, A. F., Isseroff, R. R., Griffith, T. S., Schalper, K. A., Merleev, A., Saha, A., Maverakis, E., Kelly, K., Aljumaily, R., Ibrahimi, S., Mukherjee, S., Machiorlatti, M., Vesely, S. K., Longo, D. L., Blazar, B. R., Canter, R. J., Murphy, W. J., & Monjazeb, A. M.
Affiliations
  • University of California, Davis (US)
  • University of California, San Francisco (US)
  • Sacramento VA Medical Center (US)
  • University of Minnesota (US)
  • Yale University (US)
  • UC Davis Comprehensive Cancer Center (US)
  • University of California Davis Medical Center (US)
  • University of Oklahoma Medical Center (US)
  • University of Oklahoma Health Sciences Center (US)
  • National Institute on Aging (US)
Corresponding author
Murphy, William J.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-11-12
Volume
25
Issue
1
Pages
141-151
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0221-5
PMC
PMC6324991
OpenAlex
W2898946138
Cited by
865
References
10
Citations by year
2026: 94 · 2025: 121 · 2024: 113 · 2023: 139 · 2022: 112 · 2021: 136 · 2020: 101 · 2019: 46 · 2018: 2
FWCI
26.78
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services (OD011107, P30-CA093373, P01 CA065493, CA093373)
  • National Institutes of Health (1s10od018223-01a1, CA093373, DK092993, OD-011107, CA214048, P51OD011107)
  • University of California, Davis
  • National Heart, Lung, and Blood Institute (R01HL056067, R24HL085794, HL085794, R01HL118979)
  • National Cancer Institute (R01CA195904, CA095572, R01CA095572, CA093373, CA065493, R01CA214048, P30CA225520, P30CA093373, T32CA009138, P01CA065493)
  • National Institute of Allergy and Infectious Diseases (R37AI034495)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U24DK092993)
  • California National Primate Research Center (OD 011107)
  • Comprehensive Cancer Center, University of California, Davis (P30CA093373)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
obesity, T cell function, PD-1/PD-L1 blockade, cancer immunotherapy, tumor progression, immunosenescence, leptin, T cell dysfunction, antitumor immunity
MeSH terms
Adult, Animals, Body Weight, Diet, Female, Humans, Immunotherapy, Male, Mice, Inbred C57BL, Mice, Obese, Middle Aged, Neoplasms, Obesity, Species Specificity, T-Lymphocytes, Signal Transduction, Disease Progression, Leptin, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Programmed Cell Death 1 Receptor

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