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Associations Between Infiltrating Lymphocyte Subsets and Hepatocellular Carcinoma

  • Guo, Cun-Li (The Third Hospital of Harbin Medical University) ;
  • Yang, Hai-Chao (The First Hospital of Harbin Medical University) ;
  • Yang, Xiu-Hua (The First Hospital of Harbin Medical University) ;
  • Cheng, Wen (The Third Hospital of Harbin Medical University) ;
  • Dong, Tian-Xiu (The First Hospital of Harbin Medical University) ;
  • Zhu, Wen-Jing (The First Hospital of Harbin Medical University) ;
  • Xu, Zheng (The Third Hospital of Harbin Medical University) ;
  • Zhao, Liang (The Third Hospital of Harbin Medical University)
  • Published : 2012.11.30

Abstract

Aims: We aimed to analyze the phenotype of tumor-infiltrating lymphocytes (TILs) and non-tumor infiltrating lymphocytes (NILs) in HCC and non-tumor tissues, and evaluate relationships between changes in these cells and the prognosis of HCC. Methods: Lymphocytes were isolated from HCC and corresponding non-tumor tissues and tested by flow cytometry. For comparison, clinical parameters were analyzed. Results: Compared with the non-tumor tissue, tumor tissue had a lower intensity of NK, NKT andCD8+T cell infiltration. TILs had higher intensity of CD4+CD25+Foxp3+regulatory T cell (Treg cells) infiltration compared with that in NILs. The prevalence of Treg cells was associated with fewer CD8 + T lymphocytes in the HCC immune microenvironment. The frequencies of NK cells and CD8+T cells in TILs of HCC patients with metastasis less than 12 months were lower than those without metastasis. However, the frequency of Treg cells was higher than those without metastasis. Conclusion: These results suggest that the frequencies of CD8+T, NK and NKT cells as well as Treg cells in the tumor tissue of HCC are significantly associated with patient survival, and could be applied as predictive indicators for HCC prognosis.

Keywords

References

  1. Chen CH, Lee HS, Huang GT, et al (2007). Phenotypic analysis of tumor infiltraring lymphocytes in hepatocellular carcinoma. Hepatogastroenterology, 54, 1529-33.
  2. Chew V, Tow C, Teo M, et al (2010). Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol, 52, 370-9.
  3. Fu J, Xu D, Liu Z, et al (2007). Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology, 132, 2328-39. https://doi.org/10.1053/j.gastro.2007.03.102
  4. Gao Q, Qiu SJ, Fan J, et al (2007). Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol, 25, 2586-93. https://doi.org/10.1200/JCO.2006.09.4565
  5. Gehring AJ, Ho ZZ, Tan AT, et al (2009). Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology, 137, 682-90. https://doi.org/10.1053/j.gastro.2009.04.045
  6. International Agency for Research on Cancer (2008). Liver cancer incidence and mortality worldwide in 2008. 2011; http://globocan.iarc.fr/factsheets/cancers/liver.asp.
  7. Kasper HU, Drebber U, Stippel DL, et al (2009). Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. World J Gastroenterol, 15, 5053-7. https://doi.org/10.3748/wjg.15.5053
  8. Kobayashi N, Hiraoka N, Yamagami W, et al (2007). FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res, 13, 902-11. https://doi.org/10.1158/1078-0432.CCR-06-2363
  9. Liakou CI, Narayanan S, Ng Tang D, et al (2007). Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer. Cancer Immunity, 7, 10-5.
  10. Li YW, Qiu SJ, Fan J, et al (2009). Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. J Cancer Res Clin Oncol, 135, 439-49. https://doi.org/10.1007/s00432-008-0469-0
  11. Matkowski R, Gisterek I, Halon A, et al (2009). The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res, 29, 2445-51.
  12. Nakano O, Sato M, Naito Y, et al (2001). Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res, 61, 5132-6.
  13. Okada K, Komuta K, Hashimoto S, et al (2000). Frequency of apoptosis of tumour-infiltrating lymphocytes induced by Fas counterattack in human colorectal carcinoma and its correlation with prognosis. Clin Cancer Res, 6, 3560-4.
  14. Ohmura Y, Yoshikawa K, Saga S, et al(2008). Combinations of tumor-specific CD8+ CTLs and anti-CD25 mAb provide improved immunotherapy. Oncol Rep, 19, 1265-70.
  15. Pang YL, Zhang HG, Peng JR, et al (2009). The immunosuppressive tumor microenvironment in hepatocellular carcinoma. Cancer Immunol Immunother, 58, 877-86. https://doi.org/10.1007/s00262-008-0603-5
  16. Schumacher K, Haensch W, Roefzaad C, et al (2001). Prognostic significance of activated CD8 (+) T cell infiltrations within esophageal carcinomas. Cancer Res, 61, 3932-6.
  17. Setiady YY, Coccia JA, Park PU (2010). In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcgammaRIII+ phagocytes. Eur J Immunol, 40, 780-6. https://doi.org/10.1002/eji.200939613
  18. Shen X, Li N, Li H, et al (2010). Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage. J Cancer Res Clin Oncol, 136, 1745-54. https://doi.org/10.1007/s00432-010-0833-8
  19. Shi F, Shi M, Zeng Z, et al (2011). PD-1 and PD-L1 upregulation promotes CD8 T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer, 128, 887-96. https://doi.org/10.1002/ijc.25397
  20. Shirabe K, Kanematsu T, Matsumata T, et al (1991). Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses. Hepatology, 14, 802-5. https://doi.org/10.1002/hep.1840140510
  21. Shirabe K, Matsumata T, Maeda T, et al (1995). A long-term surviving patient with hepatocellular carcinoma including lymphocytes infiltration: a clinicopathological study. Hepatogastroenterology, 42, 996-1001.
  22. Smyth MJ, Teng MW, Swann J, et al (2006). CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol, 176, 1582-7. https://doi.org/10.4049/jimmunol.176.3.1582
  23. Smyth MJ, Wallace ME, Nutt SL, et al (2005). Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J Exp Med, 201, 1973-85. https://doi.org/10.1084/jem.20042280
  24. Streuss L, Bergmann C, Whiteside TL (2009). Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol, 2, 1469-80.
  25. Unitt E, Marshall A, Gelson W, et al (2006). Tumor lymphocyte infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol, 45, 178-81. https://doi.org/10.1016/j.jhep.2006.06.005
  26. Wu K, Kryczek I, Chen L, et al (2009). Kupffer cell suppression of CD8 T cells in human hepatocellular carcinoma ismediated by B7-H1/programmed death-1 interactions. Cancer Res, 69, 8067-75. https://doi.org/10.1158/0008-5472.CAN-09-0901

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