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

Nature Medicine volume 25, pages 141–151 (2019)Cite this article

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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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Fig. 1: Obesity-related T cell dysfunction across multiple species.
Fig. 2: Obesity promotes tumor growth and T cell exhaustion.
Fig. 3: Leptin level are correlated with PD-1 expression.
Fig. 4: Lack of leptin signaling rescues T cells from exhaustion in obese mice.
Fig. 5: Improved efficacy of αPD-1 treatment in DIO mice.
Fig. 6: Exhaustion profile and improved efficacy of aPD-(L)1 immunotherapy in obese patients with cancer.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets generated during and/or analyzed during the current study are available in the NCBI BioSample repository under accession numbers SAMN09873568 and SAMN09873569.

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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Ziming Wang, Ethan G. Aguilar.

  2. These authors jointly supervised this work: William J. Murphy, Arta M. Monjazeb.

Authors and Affiliations

  1. Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA

    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, R. Rivkah Isseroff, Alexander Merleev, Emanual Maverakis & William J. Murphy

  2. Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA

    Sita S. Withers & Robert B. Rebhun

  3. Division of Experimental Medicine, University of California San Francisco, San Francisco, CA, USA

    Dennis J. Hartigan-O’Connor

  4. Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA

    Dennis J. Hartigan-O’Connor & Gema Méndez-Lagares

  5. California National Primate Research Center, University of California Davis, Davis, CA, USA

    Dennis J. Hartigan-O’Connor, Gema Méndez-Lagares & Alice F. Tarantal

  6. Department of Pediatrics, University of California Davis School of Medicine, Davis, CA, USA

    Alice F. Tarantal

  7. Department of Cell Biology and Human Anatomy, University of California Davis, Davis, CA, USA

    Alice F. Tarantal

  8. Dermatology Service, Sacramento VA Medical Center, Mather, CA, USA

    R. Rivkah Isseroff

  9. Department of Urology, Center for Immunology, Masonic Cancer Center, Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA

    Thomas S. Griffith

  10. Department of Pathology & Translational Immuno-oncology Laboratory, Yale University School of Medicine, New Haven, CT, USA

    Kurt A. Schalper

  11. Immune Monitoring Core, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Alexander Merleev & Emanual Maverakis

  12. Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Asim Saha

  13. Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis Schoolof Medicine, Sacramento, CA, USA

    Karen Kelly & William J. Murphy

  14. Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Raid Aljumaily, Sami Ibrahimi & Sarbajit Mukherjee

  15. Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Michael Machiorlatti & Sara K. Vesely

  16. Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA

    Dan L. Longo

  17. Masonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Bruce R. Blazar

  18. Division of Surgical Oncology, Department of Surgery, University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA

    Robert J. Canter

  19. Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Universityof California School of Medicine, Sacramento, CA, USA

    Arta M. Monjazeb

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  1. Ziming Wang
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  2. Ethan G. Aguilar
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Contributions

Murine studies: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., S.K.G., A.S., A.M.M. Murine studies data analysis/interpretation: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., T.S.G., D.L.L., B.R.B., R.J.C., W.J.M., A.M.M. Primate studies: D.J.H.-O’C., G.M.-L., A.F.T. Human blood donor studies: Z.W., A.M.M., K.K. Human multiplex IF: K.A.S. TCGA analysis: A.M., E.M. Clinical study: R.A., S.I., S.M., M.M., S.K.V. Overall study conception: W.J.M. Overall study design: W.J.M., A.M.M. Overall study supervision: W.J.M., A.M.M. Manuscript preparation: Z.W., E.G.A., R.J.C., W.J.M, A.M.M. Manuscript critical review: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., S.K.G., S.S.W., R.B.R., D.J.H.-O’C., G.M.-L., A.F.T., R.R.I., T.S.G., K.A.S., A.M., E.M., R.A., S.I., S.M., M.M., S.K.V., D.L.L., B.R.B., R.C., K.K.

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Wang, Z., Aguilar, E.G., Luna, J.I. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25, 141–151 (2019). https://doi.org/10.1038/s41591-018-0221-5

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