DOI QR코드

DOI QR Code

Increased Frequency of Foxp3+ Regulatory T Cells in Mice with Hepatocellular Carcinoma

  • Du, Yong (Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College) ;
  • Chen, Xin (Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College) ;
  • Huang, Zhi-Ming (Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College) ;
  • Ye, Xiao-Hua (Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College) ;
  • Niu, Qing (Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical College)
  • Published : 2012.08.31

Abstract

The CD4+CD25+ regulatory T cell (Treg) is a special kind of T cell subset. Studies have showed that Treg cells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases, transplantation tolerance and cancer. Tregs with unique capacity for immune inhibition can impair anti-tumour immunity and help tumor cells to escape from immune surveillance. The aim of our study was to investigate whether Tregs are involved in hepatocellular carcinoma (HCC). A BABL/C mouse with HCC in situ model was established to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flow cytometry and immunohistochemistry methods. Granzyme B expression in carcinoma tissues was analyzed by immunohistochemistry to investigate the tumor local immune status.The proportion of CD4+CD25+/CD4+ spleen lymphocytes of tumor bearing mice ($18.8%{\pm}1.26%$) was found to be significantly higher than that in normal mice ($9.99%{\pm}1.90%$) (P<0.01 ). Immunohistochemistry of spleen tissue also confirmed that there was an increase in Treg in tumor-bearing mice, while in carcinomas it showed Treg cells to be present in tumor infiltrating lymphocyte areas while Granzyme B was rarely observed. Anti-tumour immunity was suppressed, and this might be associated with the increase of Tregs. Our observations suggest that the CD4+CD25+Treg/CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellular carcinoma mice and the Treg may be a promising therapeutic target for cancer.

Keywords

References

  1. Berbic M, Hey-Cunningham AJ, Ng C, et al (2010). The role of Foxp3+ regulatory T-cells in endometriosis: a potential controlling mechanism for a complex, chronic immunological condition. Hum Reprod, 25, 900-7. https://doi.org/10.1093/humrep/deq020
  2. Cabrera R, Ararat M, Eksioglu EA, et al (2010). Influence of serum and soluble CD25 (sCD25) on regulatory and effector T cell function in hepatocellular carcinoma. Scand J Immunol, 72, 293-301. https://doi.org/10.1111/j.1365-3083.2010.02427.x
  3. Cao X, Cai SF, Fehniger TA, et al (2007). Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity, 27, 635-46. https://doi.org/10.1016/j.immuni.2007.08.014
  4. Cederbom L, Hall H, Lvars F (2000). CD4+CD25+ regulatory T cells down-regulate costimulatory molecules on antigenpresenting cells. Eur J Immunol, 30, 1538-43. https://doi.org/10.1002/1521-4141(200006)30:6<1538::AID-IMMU1538>3.0.CO;2-X
  5. Gao J, Xie L,Yang WS, et al (2012). Risk factors of hepatocellular carcinoma-current status and perspectives. Asian Pacific J Cancer Prev, 13, 743-52. https://doi.org/10.7314/APJCP.2012.13.3.743
  6. Ghebeh H, Barhoush E, Tulbah A (2008). Foxp3+ Tregs and B7-H1+/PD-1+T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer, 8, 50-7. https://doi.org/10.1186/1471-2407-8-50
  7. Groux H, O'Garra A, Bigler M, et al (1997). A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 389, 737-42. https://doi.org/10.1038/39614
  8. Gupta S, Joshi K, Wig JD, et al (2007) . Intratumoral FOXP3 expression in infiltrating breast carcinoma: Its association with clinicopathologic parameters and angiogenesis. Acta Oncol, 46, 792-7. https://doi.org/10.1080/02841860701233443
  9. Han Y, Guo Q, Zhang M, et al (2009). CD69+CD4+CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immmunol, 182, 111-20. https://doi.org/10.4049/jimmunol.182.1.111
  10. Herman S, Krenbek D, Klimas M, et al (2012). Regulatory T cells from stable and long-lasting cell cluster with myeloid dendritic cells(DC). Int Immunol, 24, 417-26. https://doi.org/10.1093/intimm/dxs039
  11. 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
  12. Huang YH, Zozulya AL, Weidenfeller C, et al (2009). T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible. J Leukoc Biol, 86, 273-81. https://doi.org/10.1189/jlb.1008649
  13. Junginger J, Schwittlick U, Lemensieck F, et al (2012). Immunohistochemical investigation of Foxp3 expression in the intestine in healthy and diseased dogs. Vet Res, 43, 23. https://doi.org/10.1186/1297-9716-43-23
  14. Kalos M (2003). Tumor antigen-specific T cells and cancer immunotherapy: current issues and future prospects. Vaccine, 21, 781-6. https://doi.org/10.1016/S0264-410X(02)00598-4
  15. Kiniwa Y, Miyahara Y, Wang HY, et al (2007). CD8+Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res, 13, 6947-58. https://doi.org/10.1158/1078-0432.CCR-07-0842
  16. Kudo M (2010). The 2008 Okuda lecture: Management of hepatocellular carcinoma: from surveillance to molecular targeted therapy. J Gastroenterol Hepatol, 25, 439-52. https://doi.org/10.1111/j.1440-1746.2009.06207.x
  17. Liu JY, Zhang XS, Ding Y, et al (2005). The changes of CD4+CD25+/ CD4+ proportion in spleen of tumor-bearing BALB/C mice. J Transl Med, 3, 5. https://doi.org/10.1186/1479-5876-3-5
  18. Llovet JM, Ricci S, Mazzaferro V, et al (2008). Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 359, 378-90. https://doi.org/10.1056/NEJMoa0708857
  19. Luke C, Price T, Roder D (2010). Epidemiology of cancer of the liver and intrahepatic bile ducts in an Australian population. Asian Pac J Cancer Prev, 11, 1479-85.
  20. Miller AM, Lundberg K, Ozenci V, et al (2006). CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol, 177, 7398-40. https://doi.org/10.4049/jimmunol.177.10.7398
  21. Mizukami Y, Kono K, Kawaguchi Y, et al (2008). Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer. Br J Cancer, 98, 148-53. https://doi.org/10.1038/sj.bjc.6604149
  22. Nummer D, Suri-payer E, Schmitz-Winnenthal H, et al (2007). Role of tumor endothelium in CD4+CD25+regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst, 99, 1188-99. https://doi.org/10.1093/jnci/djm064
  23. Onizuka S, Tawara I, Shimizu J, et al (1999). Tumor rejection by in vivo administration of anti-CD25( interleukin-2 receptor alpha ) monoclonal antibody. Cancer Res, 59, 3128-33.
  24. Ormandy LA, Hillemann T, Wedemeyer H, et al (2005). Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res, 65, 2457-64. https://doi.org/10.1158/0008-5472.CAN-04-3232
  25. Sakaguchi S, Sakaguchi N, Asano M, et al (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune disease. J Immunol, 155, 1151-64.
  26. Shimizu J, Yamazaki S, Sakaguchi S (1999). Induction of tumor immunity by removing CD4+CD25+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol, 163, 5211-8.
  27. Thakur S, Singla A, Chawla Y, et al (2011). Expansion of peripheral and intratumoral regulatory T cells in hepatocellular carcinoma: a case-control study. Indian J Pathol Microbiol, 54, 448-53. https://doi.org/10.4103/0377-4929.85073
  28. Trapani JA, Smyth MJ (2002). Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol, 2, 735-47. https://doi.org/10.1038/nri911
  29. Vignali DA, Collison LW, Workman CJ (2008). How regulatory T cells work. Nat Rev Immunol, 8, 523-32. https://doi.org/10.1038/nri2343
  30. Weiner HL (2001). Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev, 182, 207-14. https://doi.org/10.1034/j.1600-065X.2001.1820117.x
  31. Workman CJ, Szymczak-workman AL, Collison LW,et al (2009). The development and function of regulatory T cells. Cell Mol Life Sci, 66, 2603-22. https://doi.org/10.1007/s00018-009-0026-2
  32. Zheng SG (2008). The critical role of TGF-${\beta}1$ in the development of induced Foxp3+ regulatory T cells. Int J Clin Exp Med, 1, 192-202.
  33. Zhou J, Ding T, Pan W, et al (2009). Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer, 125, 1640-8. https://doi.org/10.1002/ijc.24556

Cited by

  1. Expression of Granulysin and FOXP3 in Cutaneous T Cell Lymphoma and Sézary Syndrome vol.16, pp.13, 2015, https://doi.org/10.7314/APJCP.2015.16.13.5359
  2. Immune Regulation by T Regulatory Cells in Hepatitis B Virus-Related Inflammation and Cancer vol.85, pp.3, 2017, https://doi.org/10.1111/sji.12524