Skip to main content
SpringerLink
Log in

Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69+ and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Roberts, D.L., C. Dive, and A.G. Renehan. 2010. Biological mechanisms linking obesity and cancer risk: new perspectives. Annual Review of Medicine 61: 301–316.

    Article  CAS  PubMed  Google Scholar 

  2. Scheen, A.J., and F.H. Luyckx. 2002. Obesity and liver disease. Best Practice & Research. Clinical Endocrinology & Metabolism 16(4): 703–716.

    Article  CAS  Google Scholar 

  3. Goran, M.I., G.D.C. Ball, and M.L. Cruz. 2003. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. The Journal of Clinical Endocrinology and Metabolism 88(4): 1417–1427.

    Article  CAS  PubMed  Google Scholar 

  4. Calle, E.E., C. Rodriguez, K. Walker-Thurmond, et al. 2003. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. The New England Journal of Medicine 348(17): 1625–1638.

    Article  PubMed  Google Scholar 

  5. Lysaght, J., E.P. van der Stok, E.H. Allott, et al. 2011. Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Letters 312: 62–72.

    Article  CAS  PubMed  Google Scholar 

  6. Lysaght, J., E.H. Allott, C.L. Donohoe, et al. 2011. T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma. British Journal of Surgery 98: 964–974.

    Article  CAS  PubMed  Google Scholar 

  7. Lynch, L.A., J.M. O’Connell, A.K. Kwasnik, et al. 2009. Are natural killer cells protecting the metabolically healthy obese patient? Obesity (Silver Spring) 17(3): 601–605.

    Article  CAS  Google Scholar 

  8. Lynch, L., D. O’Shea, D.C. Winter, et al. 2009. Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. European Journal of Immunology 39(7): 1893–1901.

    Article  CAS  PubMed  Google Scholar 

  9. Lynch, L., M. Nowak, B. Varghese, et al. 2012. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37(3): 574–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Deiuliis, J., Z. Shah, N. Shah, et al. 2011. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One. 6(1): e16376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nishimura, S., I. Manabe, M. Nagasaki, et al. 2009. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine 15(8): 914–920.

    Article  CAS  PubMed  Google Scholar 

  12. Conroy, M.J., Galvin K.C., Kavanagh, M.E., Mongan, A.M., Doyle, S.L., Gilmartin, N., Reynolds, J.V. and J. Lysaght. 2015. CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity-associated cancer. Immunol Cell Biol.

  13. Doyle, S.L., A.M. Bennett, C.L. Donohoe, et al. 2013. Establishing computed tomography-defined visceral fat area thresholds for use in obesity-related cancer research. Nutrition Research 33(3): 171–179.

    Article  CAS  PubMed  Google Scholar 

  14. Curry, M.P., S. Norris, L. Golden-Mason, et al. 2000. Isolation of lymphocytes from normal adult human liver suitable for phenotypic and functional characterisation. JIM 242: 21–31.

    CAS  Google Scholar 

  15. Ebbert, J.O., and M.D. Jensen. 2013. Fat depots, free fatty acids, and dyslipidemia. Nutrients. 5: 498–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shanahan, F. 1997. A gut reaction: lymphoepithelial communication in the intestine. Science 275(5308): 1897–1898.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, C.F., C.H. Yu, Y.M. Li, et al. 2007. Association of the frequency of peripheral natural killer T cells with nonalcoholic fatty liver disease. World Journal of Gastroenterology 13(33): 4504–4508.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Guebre-Xabier, M., S. Yang, H.Z. Lin, et al. 2000. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology 31: 633–640.

    Article  CAS  PubMed  Google Scholar 

  19. Kenna, T., L. Golden-Mason, S.A. Porcelli, et al. 2003. NKT cells from normal and tumour-bearing human livers are phenotypically and functionally distinct from murine NKT cells. Journal of Immunology 171(4): 1775–1779.

    Article  CAS  Google Scholar 

  20. Wolf, M.J., A. Adili, K. Piotrowitz, et al. 2014. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26(4): 549–564. 25.

    Article  CAS  PubMed  Google Scholar 

  21. Doherty, D.G., S. Norris, L. Madrigal-Estebas, et al. 1999. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. Journal of Immunology 163(4): 2314–2321.

    CAS  Google Scholar 

  22. Kim, D.H., D. Sandoval, J.A. Reed, E.K. Matter, E.G. Tolod, S.C. Woods, and R.J. Seeley. 2008. The role of GMCSF in adipose tissue inflammation. Am J Physiol Endicrinol Metab 295(5): 1038–1046.

    Article  Google Scholar 

  23. Gilbert and J. M. Slingerland. 2013. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annual Review of Medicine: 45–57.

  24. Lutz, C.T., and L.S. Quinn. 2012. Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Aging (Albany NY) 4(8): 535–546.

    Article  CAS  Google Scholar 

  25. Karin, M. 2009. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harbor Perspectives in Biology 1(5): 000141.

    Article  Google Scholar 

  26. Wieckowska, A., B.G. Papouchado, Z. Li, R. Lopez, N.N. Zein, and A.E. Feldstein. 2008. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. The American Journal of Gastroenterology 103: 1372–1379.

    Article  CAS  PubMed  Google Scholar 

  27. Tilg, H., and A.R. Moschen. 2011. IL-1 cytokine family members and NAFLD: neglected in metabolic liver inflammation. Journal of Hepatology 55(5): 960–962.

    Article  CAS  PubMed  Google Scholar 

  28. Yang, H., Y.H. Youm, B. Vandanmagsar, A. Ravussin, J.M. Gimble, F. Greenway, J.M. Stephens, R.L. Mynatt, and V.D. Dixit. 2010. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. Journal of Immunology 185(3): 1836–1845.

    Article  CAS  Google Scholar 

  29. Barra, N.G., S. Reid, R. MacKenzie, G. Werstuck, B.L. Trigatti, C. Richards, A.C. Holloway, and A.A. Ashkar. 2010. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity 18: 1601–1607.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors would like to thank all of the patients attending the Oesophageal Unit at St. James’s Hospital, Dublin, for their participation in this study.

Author information

Authors and Affiliations

  1. Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland

    Melissa J. Conroy, Karen C. Galvin, Suzanne L. Doyle, Maria E. Kavanagh, Ann-Marie Mongan, Aoife Cannon, Gillian Y. Moore, John V. Reynolds & Joanne Lysaght

  2. Oesophageal Unit, St. James’s Hospital, Dublin, Ireland

    John V. Reynolds

  3. School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland

    Suzanne L. Doyle

Authors
  1. Melissa J. Conroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen C. Galvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzanne L. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria E. Kavanagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann-Marie Mongan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aoife Cannon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gillian Y. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John V. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joanne Lysaght
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanne Lysaght.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by the Health Research Board of Ireland Health Research Award HRA_POR/2011/91.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

ELECTRONIC SUPPLEMENTARY MATERIAL

Below is the link to the electronic supplementary material.

Supplemental Data Figure 1

Representative dotplots showing the gating strategy for surface marker expression and intracellular cytokine expression by T lymphocytes. a (Left-Right): For surface marker quantification, forward scatter and side scatter were first used to gate on lymphocytes, followed by gating of CD8+ CD4- lymphocytes and CD8- CD4+ lymphocytes. CD62L was then quantified as a percentage of either CD8+ CD4- lymphocytes or CD8- CD4+ lymphocytes. b (Left-Right): For intracellular cytokine quantification, forward scatter and side scatter were first used to gate on lymphocyte gate, followed by gating of CD8+ CD3+ lymphocytes and CD8- CD3+ lymphocytes. TNF-α+ cells were then quantified as a percentage of CD8+ CD3+ lymphocytes or CD8- CD3+ lymphocytes. (TIF 295 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conroy, M.J., Galvin, K.C., Doyle, S.L. et al. Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients. Inflammation 39, 1729–1736 (2016). https://doi.org/10.1007/s10753-016-0407-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0407-2

KEY WORDS

Search

Navigation