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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

  2. 2.

    Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

  3. 3.

    Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

  4. 4.

    Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

  5. 5.

    Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

  6. 6.

    Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

  7. 7.

    Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).

  8. 8.

    Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

  9. 9.

    Mehnert, J. M. et al. The challenge for development of valuable immuno-oncology biomarkers. Clin. Cancer Res. 23, 4970–4979 (2017).

  10. 10.

    Tao, W. & Lagergren, J. Clinical management of obese patients with cancer. Nat. Rev. Clin. Oncol. 10, 519–533 (2013).

  11. 11.

    Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A. & Hsueh, W. A. Obesity, inflammation, and cancer. Annu. Rev. Pathol. 11, 421–449 (2016).

  12. 12.

    Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

  13. 13.

    Cawley, J. & Meyerhoefer, C. The medical care costs of obesity: an instrumental variables approach. J. Health Econ. 31, 219–230 (2012).

  14. 14.

    McQuade, J. L. et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 19, 310–322 (2018).

  15. 15.

    Albiges, L. et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J. Clin. Oncol. 34, 3655–3663 (2016).

  16. 16.

    Nunez, N. P. et al. Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones. Nutr. Cancer 60, 534–541 (2008).

  17. 17.

    Deiuliis, J. et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6, e16376 (2011).

  18. 18.

    Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).

  19. 19.

    Buggert, M. et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS. Pathog. 10, e1004251 (2014).

  20. 20.

    Crawford, A. et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40, 289–302 (2014).

  21. 21.

    Kao, C. et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat. Immunol. 12, 663 (2011).

  22. 22.

    Shirakawa, K. et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J. Clin. Invest. 126, 4626–4639 (2016).

  23. 23.

    Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

  24. 24.

    Crespo, J., Sun, H., Welling, T. H., Tian, Z. & Zou, W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 25, 214–221 (2013).

  25. 25.

    Naylor, C. & Petri, W. A. Jr Leptin regulation of immune responses. Trends Mol. Med. 22, 88–98 (2016).

  26. 26.

    Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C. & MacIver, N. J. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol. 192, 136–144 (2014).

  27. 27.

    Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).

  28. 28.

    Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–743 (2004).

  29. 29.

    Liu, B. et al. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G573–G584 (2013).

  30. 30.

    Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

  31. 31.

    Lee, G.-H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

  32. 32.

    Chinai, J. M. et al. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol. Sci. 36, 587–595 (2015).

  33. 33.

    Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C. & MacIver, N. J. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol. 192, 136–144 (2014).

  34. 34.

    Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).

  35. 35.

    Lee, J. H., Reed, D. R. & Price, R. A. Leptin resistance is associated with extreme obesity and aggregates in families. Int. J. Obesity Relat. Metab. Disord. 25, 1471–1473 (2001).

  36. 36.

    Myers, M. G., Leibel, R. L., Seeley, R. J. & Schwartz, M. W. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 21, 643–651 (2010).

  37. 37.

    Lord, G. M., Matarese, G., Howard, J. K., Bloom, S. R. & Lechler, R. I. Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines. J Leukoc. Biol. 72, 330–338 (2002).

  38. 38.

    Kleffel, S. et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242–1256 (2015).

  39. 39.

    Li, H. Y. et al. The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1/PD-L1 antibody blockade. Cancer Immunol Res. 5, 767–777 (2017).

  40. 40.

    Mirsoian, A. et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 211, 2373–2383 (2014).

  41. 41.

    Amjadi, F., Javanmard, S. H., Zarkesh-Esfahani, H., Khazaei, M. & Narimani, M. Leptin promotes melanoma tumor growth in mice related to increasing circulating endothelial progenitor cells numbers and plasma NO production. J. Exp. Clin. Canc. Res. 30, 21 (2011).

  42. 42.

    Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

  43. 43.

    Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016).

  44. 44.

    Bates, S. H. et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–859 (2003).

  45. 45.

    Buettner, C. et al. Critical role of STAT3 in leptin’s metabolic actions. Cell. Metab. 4, 49–60 (2006).

  46. 46.

    Austin, J. W., Lu, P., Majumder, P., Ahmed, R. & Boss, J. M. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J. Immunol. 192, 4876–4886 (2014).

  47. 47.

    Bally, A. P. R., Austin, J. W. & Boss, J. M. Genetic and epigenetic regulation of PD-1 Expression. J. Immunol. 196, 2431–2437 (2016).

  48. 48.

    Bu, L. L. et al. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC. J. Dent. Res. 96, 1027–1034 (2017).

  49. 49.

    Clements, V. K. et al. Frontline Science: high fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells. J. Leukoc. Biol. 103, 395–407 (2018).

  50. 50.

    Mirsoian, A. et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J. Exp. Med. 211, 2373–2383 (2014).

  51. 51.

    Bouchlaka, M. N. et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J. Exp. Med. 210, 2223–2237 (2013).

  52. 52.

    Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

  53. 53.

    Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

  54. 54.

    Warde-Farley, D. et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38, W214–W220 (2010).

  55. 55.

    Villarroel-Espindola, F. et al. Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res. 24, 1562–1573 (2017).

  56. 56.

    Cava, C. et al. SpidermiR: An R/Bioconductor package for integrative analysis with miRNA data. Int. J. Mol. Sci. 18, 274 (2017).

  57. 57.

    Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome. Biol. 15, 550 (2014).

Download references

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.

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

Authors

  1. Search for Ziming Wang in:

  2. Search for Ethan G. Aguilar in:

  3. Search for Jesus I. Luna in:

  4. Search for Cordelia Dunai in:

  5. Search for Lam T. Khuat in:

  6. Search for Catherine T. Le in:

  7. Search for Annie Mirsoian in:

  8. Search for Christine M. Minnar in:

  9. Search for Kevin M. Stoffel in:

  10. Search for Ian R. Sturgill in:

  11. Search for Steven K. Grossenbacher in:

  12. Search for Sita S. Withers in:

  13. Search for Robert B. Rebhun in:

  14. Search for Dennis J. Hartigan-O’Connor in:

  15. Search for Gema Méndez-Lagares in:

  16. Search for Alice F. Tarantal in:

  17. Search for R. Rivkah Isseroff in:

  18. Search for Thomas S. Griffith in:

  19. Search for Kurt A. Schalper in:

  20. Search for Alexander Merleev in:

  21. Search for Asim Saha in:

  22. Search for Emanual Maverakis in:

  23. Search for Karen Kelly in:

  24. Search for Raid Aljumaily in:

  25. Search for Sami Ibrahimi in:

  26. Search for Sarbajit Mukherjee in:

  27. Search for Michael Machiorlatti in:

  28. Search for Sara K. Vesely in:

  29. Search for Dan L. Longo in:

  30. Search for Bruce R. Blazar in:

  31. Search for Robert J. Canter in:

  32. Search for William J. Murphy in:

  33. Search for Arta M. Monjazeb in:

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.

Competing interests

The authors have no competing interests to declare.

Corresponding author

Correspondence to William J. Murphy.

Supplementary Information

  1. Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 1–3

  2. Reporting Summary

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41591-018-0221-5