Article | Published:

Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF

Nature Cell Biology volume 19, pages 974987 (2017) | Download Citation

Abstract

Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

  2. 2.

    & Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  3. 3.

    & The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014).

  4. 4.

    et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

  5. 5.

    , & Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  6. 6.

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

  7. 7.

    et al. American Society of Clinical Oncology position statement on obesity and cancer. J. Clin. Oncol. 32, 3568–3574 (2014).

  8. 8.

    Adipose tissue, adipokines, and inflammation. J. Allergy Clin. Immunol. 115, 911–919 (2005).

  9. 9.

    et al. Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity. J. Biol. Chem. 286, 23591–23599 (2011).

  10. 10.

    & Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).

  11. 11.

    , & Obesity and inflammation: new insights into breast cancer development and progression. Am. Soc. Clin. Oncol. Educ. Book 33, 46–51 (2013).

  12. 12.

    et al. Systemic correlates of white adipose tissue inflammation in early-stage breast cancer. Clin. Cancer Res. 22, 2283–2289 (2015).

  13. 13.

    & Inflammation and cancer. Nature 420, 860–867 (2002).

  14. 14.

    et al. Effect of obesity on prognosis after early-stage breast cancer. J. Clin. Oncol. 29, 25–31 (2011).

  15. 15.

    & Obesity correlation with metastases development and response to first-line metastatic chemotherapy in breast cancer. Clin. Med. Insights Oncol. 9, 105–112 (2015).

  16. 16.

    , & Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).

  17. 17.

    , & Breast cancer metastasis: markers and models. Nat. Rev. Cancer 5, 591–602 (2005).

  18. 18.

    Obesity and lung inflammation. J. Appl. Physiol. 108, 722–728 (2010).

  19. 19.

    , & The impact of diet on asthma and allergic diseases. Nat. Rev. Immunol. 15, 308–322 (2015).

  20. 20.

    & Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28 (2016).

  21. 21.

    et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 3, 578–589 (2013).

  22. 22.

    et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).

  23. 23.

    et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).

  24. 24.

    & Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

  25. 25.

    et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).

  26. 26.

    et al. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J. Immunol. 194, 5529–5538 (2015).

  27. 27.

    et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

  28. 28.

    et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

  29. 29.

    et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+ Ly6C+ granulocytes. Proc. Natl Acad. Sci. USA 107, 21248–21255 (2010).

  30. 30.

    et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

  31. 31.

    et al. Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56, 1129–1139 (2013).

  32. 32.

    , & Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

  33. 33.

    et al. Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling. J. Immunol. 187, 911–918 (2011).

  34. 34.

    , , & CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 120, 2423–2431 (2010).

  35. 35.

    & Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat. Med. 9, 315–321 (2003).

  36. 36.

    et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

  37. 37.

    et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

  38. 38.

    et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. 170, 270–278 (2003).

  39. 39.

    , , & Antigen-specific inhibition of CD8 + T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).

  40. 40.

    , , & Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67, 4507–4513 (2007).

  41. 41.

    et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821–835 (2014).

  42. 42.

    et al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J. Immunol. 181, 4666–4675 (2008).

  43. 43.

    et al. Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discov. 6, 630–649 (2016).

  44. 44.

    et al. Gr-1+ CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 70, 6139–6149 (2010).

  45. 45.

    et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014).

  46. 46.

    , , & Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia. Eur. J. Haematol. 76, 516–520 (2006).

  47. 47.

    et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994).

  48. 48.

    et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994).

  49. 49.

    et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N. Engl. J. Med. 356, 567–579 (2007).

  50. 50.

    et al. IL-5, IL-8 and GM-CSF immunostaining of sputum cells in bronchial asthma and chronic bronchitis. Clin. Exp. Allergy 25, 720–728 (1995).

  51. 51.

    & The immunology of asthma. Nat. Immunol. 16, 45–56 (2015).

  52. 52.

    et al. The IL-3/IL-5/GM-CSF common receptor plays a pivotal role in the regulation of Th2 immunity and allergic airway inflammation. J. Immunol. 180, 1199–1206 (2008).

  53. 53.

    , & Eosinophils: changing perspectives in health and disease. Nat. Rev. Immunol. 13, 9–22 (2013).

  54. 54.

    et al. Interleukin 5 is protective during sepsis in an eosinophil-independent manner. Am. J. Respir. Crit. Care Med. 186, 246–254 (2012).

  55. 55.

    , , , & Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J. Clin. Invest. 104, 657–667 (1999).

  56. 56.

    , & The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent. J. Immunol. 166, 6982–6991 (2001).

  57. 57.

    et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541, 81–86 (2017).

  58. 58.

    et al. Effects of rapid weight loss on systemic and adipose tissue inflammation and metabolism in obese postmenopausal women. J. Endocr. Soc. 1, 625–637 (2017).

  59. 59.

    et al. Serum C-reactive protein and white blood cell count in morbidly obese surgical patients. Obes. Surg. 19, 461–466 (2009).

  60. 60.

    et al. Tumor growth factor expression in obesity and changes in expression with weight loss: another cause of increased virulence and incidence of cancer in obesity. Surg. Obes. Relat. Dis. 6, 538–541 (2010).

  61. 61.

    et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).

  62. 62.

    et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

  63. 63.

    , & Mepolizumab in the treatment of severe eosinophilic asthma. Immunotherapy 8, 27–34 (2016).

  64. 64.

    et al. Caloric restriction reverses obesity-induced mammary gland inflammation in mice. Cancer Prev. Res. 6, 282–289 (2013).

  65. 65.

    et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

  66. 66.

    et al. A mouse GM-CSF receptor antibody attenuates neutrophilia in mice exposed to cigarette smoke. Eur. Respir. J. 38, 285–294 (2011).

  67. 67.

    et al. Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment. Cancer Res. 75, 1624–1634 (2015).

  68. 68.

    et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114, 427–437 (2004).

  69. 69.

    et al. Leptin and adiponectin modulate the self-renewal of normal human breast epithelial stem cells. Cancer Prev. Res. 8, 1174–1183 (2015).

  70. 70.

    & Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments. J. Vis. Exp. 77, e50586 (2013).

Download references

Acknowledgements

We thank members of the Joyce and Dannenberg laboratories and V. Mittal for insightful comments and discussion. We acknowledge J. O. Alemán for assistance in providing human sera from weight loss trials. We thank H.-W. Wang for originally isolating the PyMT-BL6 cell lines used herein, and F. Klemm and J. Kowal for critically reading the manuscript. This research was supported by the Breast Cancer Research Foundation (J.A.J., A.J.D.), the Ludwig Institute for Cancer Research (J.A.J.), NIH/NCI U54 CA210184-01 (A.J.D.), the Botwinick-Wolfensohn Foundation (in memory of Mr and Mrs Benjamin Botwinick) (A.J.D.), the Sackler Center for Biomedicine and Nutrition Research at The Rockefeller University (P.R.H.), a National Cancer Institute Cancer Center Support Grant awarded to MSKCC (P30 CA008748), and fellowships from the Canadian Institutes of Health Research (D.F.Q., L.A.W.), National Cancer Institute F31CA171384 (O.C.O.), and the American Brain Tumor Association in honour of Joel A. Gingras (L.A.).

Author information

Author notes

    • Daniela F. Quail
    •  & Oakley C. Olson

    These authors contributed equally to this work.

Affiliations

  1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Daniela F. Quail
    • , Oakley C. Olson
    • , Leila Akkari
    • , Marsha L. Quick
    • , Nir Ben-Chetrit
    •  & Johanna A. Joyce
  2. Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Priya Bhardwaj
    • , I-Chun Chen
    • , Nils Wendel
    • , Nir Ben-Chetrit
    •  & Andrew J. Dannenberg
  3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Logan A. Walsh
  4. Ludwig Institute for Cancer Research, Lausanne 1066, Switzerland

    • Leila Akkari
    •  & Johanna A. Joyce
  5. Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland

    • Leila Akkari
    •  & Johanna A. Joyce
  6. Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York 10065, USA

    • Jeanne Walker
    •  & Peter R. Holt

Authors

  1. Search for Daniela F. Quail in:

  2. Search for Oakley C. Olson in:

  3. Search for Priya Bhardwaj in:

  4. Search for Logan A. Walsh in:

  5. Search for Leila Akkari in:

  6. Search for Marsha L. Quick in:

  7. Search for I-Chun Chen in:

  8. Search for Nils Wendel in:

  9. Search for Nir Ben-Chetrit in:

  10. Search for Jeanne Walker in:

  11. Search for Peter R. Holt in:

  12. Search for Andrew J. Dannenberg in:

  13. Search for Johanna A. Joyce in:

Contributions

D.F.Q., O.C.O. and J.A.J. conceived the study, designed and interpreted experiments, and wrote the manuscript. D.F.Q., O.C.O., P.B., L.A.W., L.A., M.L.Q., I.-C.C., N.W. and N.B.-C. performed experiments and analysed results. J.W., P.R.H. and A.J.D. provided human sera and blood, and A.J.D. helped design and interpret experiments. J.A.J. supervised the study. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johanna A. Joyce.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

  2. 2.

    Supplementary Information

    Supplementary Information

Excel files

  1. 1.

    Supplementary Table 1

    Supplementary Information

  2. 2.

    Supplementary Table 2

    Supplementary Information

  3. 3.

    Supplementary Table 3

    Supplementary Information

  4. 4.

    Supplementary Table 4

    Supplementary Information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncb3578

Further reading