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Expression of Fas/FasL in CD8+ T and CD3+ Foxp3+ Treg Cells - Relationship with Apoptosis of Circulating CD8+ T Cells in Hepatocellular Carcinoma Patients

  • Guo, Cun-Li ;
  • Yang, Xiu-Hua ;
  • Cheng, Wen ;
  • Xu, Yi ;
  • Li, Jie-Bing ;
  • Sun, Yi-Xin ;
  • Bi, Yu-Mei ;
  • Zhang, Lei ;
  • Wang, Qiu-Cheng
  • Published : 2014.03.30

Abstract

Aims: Dysfunction of the host immune system in cancer patients can be due to a number of factors, including lymphocyte apoptosis. Several studies showed that $Foxp3^+T$ cells take part in inducing this process by expressing FasL in tumor patients. However, the relationship between apoptosis, $CD8^+T$ cells and $Foxp3^+T$ cells in HCC patients is still unclear. The present study was designed to investigate the correlation between apoptosis levels and Fas/FasL expression in $CD8^+T$ lymphocytes and $Foxp3^+T$ cells in patients with HCC. Methods: $CD8^+T$ cells and $CD3^+Foxp3^+T$ cells were tested from peripheral blood of HCC patients and normal controls and subjected to multicolor flow cytometry. The expression of an apoptosis marker (annexin V) and the death receptor Fas in $CD8^+T$ cells and FasL in $CD3^+Foxp3^+T$ cells were evaluated. Serum TGF-${\beta}1$ levels in patients with HCC were measured by enzyme-linked immunosorbent assay. The relationship between apoptosis and Fas expression, as well as FasL expression in $CD3^+Foxp3^+T$ cells was then evaluated. Results: The frequency of $CD8^+T$ cells binding annexin V and Fas expression in $CD8^+T$ cells, were all higher in HCC patients than normal controls and the proportion of apoptotic $CD8^+T$ cells correlated with their Fas expression. Serum TGF-${\beta}1$ levels correlated inversely with $CD3^+Foxp3^+T$ cells. Conclusions: Fas/FasL interactions might lead to excessive turnover of $CD8^+T$ cells and reduce anti-tumor immune responses in patients with HCC. Further investigations of apoptosis induction in $Fas^+CD8^+T$ cells in vitro are required.

Keywords

Hepatocellular carcinoma;$CD8^+T$ lymphocytes-$CD3^+Foxp3^+T$ cells;apoptosis;Fas;Fas ligand

References

  1. Rauf A, Khatri M, Murgia MV, et al (2012). Fas/FasL and perforin-granzyme pathways mediated T cell cytotoxic responses in infectious bursal disease virus infected chickens. Results Immunol, 2, 112-9. https://doi.org/10.1016/j.rinim.2012.05.003
  2. Yang ZQ, Yang ZY, Zhang LD, et al (2010). Increased liver-infiltrating $CD8^{+}FoxP3^{+}$ regulatory T cells are associated with tumor stage in hepatocellular carcinoma patients. Hum Immunol, 71, 1180-6. https://doi.org/10.1016/j.humimm.2010.09.011
  3. Yoshikawa T, Saito H, Os aki T, et al (2008). Elevated Fas expression is related to increased apoptosis of circulating $CD8^{+}$T cell in patients with gastric cancer. J Surg Res, 148, 143-51. https://doi.org/10.1016/j.jss.2007.07.011
  4. Liu Y, Peng Y, Mi M, et al (2009). Lentivector immunization stimulates potent CD8 T cell responses against melanoma self-antigen tyrosinase-related protein 1 and generates antitumor immunity in mice. J Immunol, 10, 5960-9.
  5. Nakamura S, Yaguchi T, Kawamura N, et al (2014). TGF-$\beta$1 in Tumor Microenvironments Induces Immunosuppression in the Tumors and Sentinel Lymph Nodes and Promotes Tumor Progression. J Immunother, 2, 63-72.
  6. Pages F, Galon J, Dieu-Nosjean MC, et al (2010). Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene, 29,1093-102. https://doi.org/10.1038/onc.2009.416
  7. Reichert TE, Strauss L, Wagner EM, et al (2002). Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin Cancer Res, 8, 3137-45.
  8. Schramm C, Huber S, Protschka M, et al (2004). TGF-beta regulates the $CD4^{+}CD25^{+}$T-cell pool and the expression of Foxp3 in vivo. Int Immunol, 16, 1241-9. https://doi.org/10.1093/intimm/dxh126
  9. Strauss L, Bergmann C, Whiteside TL (2009). Human circulating $CD4^{+}CD25$ high $Foxp3^{+}$ regulatory T cells kill autologous $CD8^{+}$ but not $CD4^{+}$ responder cells by Fas-mediated aptosis. J Immunol, 182, 1469-80. https://doi.org/10.4049/jimmunol.182.3.1469
  10. Wang WJ, Tao Z, Gu W, et al (2013). Variation of blood T lymphocyte subgroups in patients with non-small cell lung cancer. Asian Pac J Cancer Prev, 8, 4671-3.
  11. Wolf D, Wolf AM, Rumpold H, et al (2005). The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res, 11, 8326-31. https://doi.org/10.1158/1078-0432.CCR-05-1244
  12. Janssens W, Carlier V, Wu B, et al (2003). $CD4^{+}CD25^{+}$T cells lyse antigen-presenting B cells by Fas-Fas ligand interaction in an epitope-specific maIlller. J Immunol, 171, 4604-12. https://doi.org/10.4049/jimmunol.171.9.4604
  13. Horwitz DA, Pan S, OuJN, et al (2013). Therapeutic polyclonal human $CD8^{+}CD25^{+}Fox3^{+}TNFR2^{+}PD^{-}L1^{+}$ regulatory cells induced ex-vivo. Clin Immunol, 3, 50-63.
  14. Hu JL, Yang Z, Tang JR, et al (2013). Effects of gastric cancer cells on the differentiation of Treg cells. Asian Pac J Cancer Prev, 8, 4607-10.
  15. Jang TJ (2013). Progressive increase of regulatory T cells and decrease of $CD8^{+}$T cells and $CD8^{+}$T cellslregulatory T cells ratio during colorectal cancer development. Korean J Pathol, 5, 443-51.
  16. KassoufN, Thomhill MH (2008). Oral cancer cell lines can use multiple ligands, including Fas-L, TRAIL and TNF-alpha, to induce apoptosis in Jurkat T cells: possible mechanisms for immune escape by head and neck cancers. Oral Oncol, 7, 672-82.
  17. Kerkar SF, Restifo NP (2012). Cellular constituents of immune escape within the tumor microenvironment. Cancer Res, 13,3125-30.
  18. Khattri R, Cox T, Yasayko SA, et al (2003).An essential role for Scurfin in $CD4^{+}CD25^{+}$T regulatory cells. Nat Immunol, 4,337-42.
  19. Lin Y, Liu L, Zhang T, et al (2013). Functional investigation of Fas ligand expressions in human non-small cell lung cancer cells and its clinical implications. Ann Thorac Surg, 2, 412-8.
  20. Liu VC, Wong LY, Jang T, et al (2007). Tumor evasion of the immune system by converting $CD4^{+}CD25^{-}$T cells into $CD4^{+}CD25^{+}$T regulatory cells: role of tumor-derived TGF-beta. J Immunol, 178, 2883-92. https://doi.org/10.4049/jimmunol.178.5.2883
  21. Ferrone S, Whiteside TL (2007). Tumor microenvironment and immune escape. Surg Oncol Clin N Am, 16,755-74. https://doi.org/10.1016/j.soc.2007.08.004
  22. Bauernhofer T, Kuss I, Henderson B, et al (2003). Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol, 33, 119-24. https://doi.org/10.1002/immu.200390014
  23. Chen W, Jin W, Hardegen N, et al (2003). Conversion of peripheral $CD4^{+}CD25^{-}$ naive T cells to $CD4^{+}CD25^{+}$ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 198, 1875-86. https://doi.org/10.1084/jem.20030152
  24. Fang Ll , Sun L, Hu FF, et al (2013).Effects of FasL expression in oral squamous cell cancer. Asian Pac J Cancer Prev, 1, 281-5.
  25. Fontenot JD, Gavin MA, Rudensky AY (2003). Foxp3 programs the development and function of $CD4^{+}CD25^{+}$ regulatory T cells. Nat Immunol, 4, 330-6. https://doi.org/10.1038/ni904
  26. Gogali F, Paterakis G, Rassidakis GZ, et al (2012). Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NKcells in the papillary carcinoma of thyroid. J Clin Endocrinol Metab, 5, 1474-82.
  27. Grossman WJ, Verbsky JW, Barchet W, et al (2004). Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity, 21, 589-601. https://doi.org/10.1016/j.immuni.2004.09.002
  28. Guo CL, Yang HC, Yang XH, et al (2012). Associations between infiltrating lymphocyte subsets and hepatocellular carcinoma. Asian Pac J Cancer Prev, 11, 5909-13.
  29. Hoffmann TK, Dworacki G, Tsukihiro T, et al (2002). Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res, 8, 2553-62.
  30. Hori S, Nomura T, Sakaguchi S (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299, 1057-61. https://doi.org/10.1126/science.1079490
  31. AbusamraAJ, Zhong Z, Zheng X, et al (2005). Tumor exosomes expressing Fas ligand mediate $CD8^{+}$T-cell apoptosis. Blood cells Mol Dis, 35, 169-73. https://doi.org/10.1016/j.bcmd.2005.07.001

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Acknowledgement

Supported by : China National Science Foundation