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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.

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.

References

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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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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  3. Jesus I. Luna
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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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