Metabolic reprogramming of natural killer cells in obesity limits antitumor responses

Abstract

Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete ‘paralysis’ of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell–tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: NK cells from HFD mice show upregulation of lipid metabolism-related genes and downregulation of the killing machinery.
Fig. 2: Obesity leads to NK cell loss of function and lipid accumulation.
Fig. 3: Lipid uptake and accumulation leads to NK cell loss of function.
Fig. 4: Lipid accumulation during obesity impairs mTOR pathway.
Fig. 5: Lipid accumulation during obesity negatively impacts NK cell metabolism.
Fig. 6: Activation of the PPARα/δ pathway induces functional and metabolic defects in NK cells.
Fig. 7: The decreased ability of NK cells to kill tumor cells in obesity is related to a defect of lytic granule polarization and can be reversed with metabolic reprograming.
Fig. 8: Lipid uptake reduces NK cell antitumor activity in vivo.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Global status report on noncommunicable diseases 2014 (WHO, 2004).

  2. 2.

    Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591 (2004).

    CAS  Article  Google Scholar 

  3. 3.

    Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).

    Article  Google Scholar 

  4. 4.

    Falagas, M. E. & Kompoti, M. Obesity and infection. Lancet. Infect. Dis. 6, 438–446 (2006).

    Article  Google Scholar 

  5. 5.

    Sjostrom, L. et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 10, 653–662 (2009).

    Article  Google Scholar 

  6. 6.

    Renehan, A. G., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat. Rev. Cancer 15, 484–498 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).

    CAS  Article  Google Scholar 

  9. 9.

    Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).

    CAS  Article  Google Scholar 

  11. 11.

    Mace, E. M. et al. Cell biological steps and checkpoints in accessing NK cell cytotoxicity. Immunol. Cell Biol. 92, 245–255 (2014).

    CAS  Article  Google Scholar 

  12. 12.

    Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 8, 713–725 (2008).

    CAS  Article  Google Scholar 

  13. 13.

    Chowdhury, D. & Lieberman, J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu. Rev. Immunol. 26, 389–420 (2008).

    CAS  Article  Google Scholar 

  14. 14.

    Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014).

    CAS  Article  Google Scholar 

  15. 15.

    Marcais, A. et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014).

    CAS  Article  Google Scholar 

  16. 16.

    Bjorntorp, P., Bergman, H. & Varnauskas, E. Plasma free fatty acid turnover rate in obesity. Acta Med. Scand. 185, 351–356 (1969).

    CAS  Article  Google Scholar 

  17. 17.

    Jensen, M. D., Haymond, M. W., Rizza, R. A., Cryer, P. E. & Miles, J. M. Influence of body fat distribution on free fatty acid metabolism in obesity. J. Clin. Invest. 83, 1168–1173 (1989).

    CAS  Article  Google Scholar 

  18. 18.

    Lynch, L. A. et al. Are natural killer cells protecting the metabolically healthy obese patient? Obesity (Silver Spring) 17, 601–605 (2009).

    CAS  Article  Google Scholar 

  19. 19.

    O’Shea, D., Cawood, T. J., O’Farrelly, C. & Lynch, L. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke. PloS ONE 5, e8660 (2010).

    Article  Google Scholar 

  20. 20.

    Jahn, J. et al. Decreased NK cell functions in obesity can be reactivated by fat mass reduction. Obesity (Silver Spring) 23, 2233–2241 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Perdu, S. et al. Maternal obesity drives functional alterations in uterine NK cells. JCI Insight 1, e85560 (2016).

    Article  Google Scholar 

  22. 22.

    Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    CAS  Article  Google Scholar 

  23. 23.

    Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).

    CAS  Article  Google Scholar 

  24. 24.

    Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    CAS  Article  Google Scholar 

  25. 25.

    Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).

    CAS  Article  Google Scholar 

  26. 26.

    Lefebvre, P., Chinetti, G., Fruchart, J. C. & Staels, B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J. Clin. Invest. 116, 571–580 (2006).

    CAS  Article  Google Scholar 

  27. 27.

    Barber, D. F., Faure, M. & Long, E. O. LFA-1 contributes an early signal for NK cell cytotoxicity. J. Immunol. 173, 3653–3659 (2004).

    CAS  Article  Google Scholar 

  28. 28.

    Mace, E. M., Monkley, S. J., Critchley, D. R. & Takei, F. A dual role for talin in NK cell cytotoxicity: activation of LFA-1-mediated cell adhesion and polarization of NK cells. J. Immunol. 182, 948–956 (2009).

    CAS  Article  Google Scholar 

  29. 29.

    James, A. M. et al. Rapid activation receptor- or IL-2-induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling. Blood 121, 2627–2637 (2013).

    CAS  Article  Google Scholar 

  30. 30.

    Mentlik, A. N., Sanborn, K. B., Holzbaur, E. L. & Orange, J. S. Rapid lytic granule convergence to the MTOC in natural killer cells is dependent on dynein but not cytolytic commitment. Mol. Biol. Cell 21, 2241–2256 (2010).

    CAS  Article  Google Scholar 

  31. 31.

    Liu, D., Martina, J. A., Wu, X. S., Hammer, J. A. 3rd & Long, E. O. Two modes of lytic granule fusion during degranulation by natural killer cells. Immunol. Cell Biol. 89, 728–738 (2011).

    CAS  Article  Google Scholar 

  32. 32.

    Menager, M. M. et al. Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat. Immunol. 8, 257–267 (2007).

    CAS  Article  Google Scholar 

  33. 33.

    Tuli, A. et al. Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell-mediated cytotoxicity. Mol. Biol. Cell 24, 3721–3735 (2013).

    CAS  Article  Google Scholar 

  34. 34.

    Kupfer, A., Dennert, G. & Singer, S. J. Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proc. Natl Acad. Sci. USA 80, 7224–7228 (1983).

    CAS  Article  Google Scholar 

  35. 35.

    Boden, G. & Shulman, G. I. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur. J. Clin. Invest. 32, 14–23 (2002).

    CAS  Article  Google Scholar 

  36. 36.

    Boulenouar, S. et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity 46, 273–286 (2017).

    CAS  Article  Google Scholar 

  37. 37.

    Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015).

    CAS  Article  Google Scholar 

  38. 38.

    O’Sullivan, T. E. et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45, 428–441 (2016).

    Article  Google Scholar 

  39. 39.

    Lee, B. C. et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 23, 685–698 (2016).

    CAS  Article  Google Scholar 

  40. 40.

    Muller, A. J. et al. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc. Natl Acad. Sci. USA 105, 17073–17078 (2008).

    CAS  Article  Google Scholar 

  41. 41.

    Allison, D. J. & Ditor, D. S. Immune dysfunction and chronic inflammation following spinal cord injury. Spinal Cord 53, 14–18 (2015).

    CAS  Article  Google Scholar 

  42. 42.

    Gentile, L. F. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute Care Surg. 72, 1491–1501 (2012).

    CAS  Article  Google Scholar 

  43. 43.

    Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016).

    CAS  Article  Google Scholar 

  44. 44.

    Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    CAS  Article  Google Scholar 

  45. 45.

    Cohen, N. R. et al. Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nat. Immunol. 14, 90–99 (2013).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank M. Wilk and J. Barrett for assistance with experiments. This research was supported by National Institutes of Health (NIH) grant R01 AI11304603 (M.B.B.), European Research Council (ERC) Starting Grant 679173, a Cancer Research Institute CLIP grant and 16/FRL/3865 (L.L.).

Author information

Affiliations

Authors

Contributions

X.M., L.D., and L.L. conceived and designed the experiments, and wrote the manuscript. X.M., L.D., A.H., R.M.L., D.D., K.W., R.D., M.R., and L.L. performed the experiments. C.F. performed the RNA-seq analysis. A.T., A.V., W.P., D.O.’S., and B.S.N. obtained patient samples and coordinated the clinical investigations. S.B., C.O.F., K.H.G.M., M.B.B., and D.F. provided advice, reagents and critical insight.

Corresponding author

Correspondence to Lydia Lynch.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Michelet, X., Dyck, L., Hogan, A. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol 19, 1330–1340 (2018). https://doi.org/10.1038/s41590-018-0251-7

Download citation

Further reading