Presence of Tumour-infiltrating FOXP3+ Lymphocytes Correlates with Immature Tumour Angiogenesis in Renal Cell Carcinomas

  • Zhan, Hai-Lun (Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University) ;
  • Gao, Xin (Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University) ;
  • Zhou, Xiang-Fu (Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University) ;
  • Pu, Xiao-Yong (Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University) ;
  • Wang, De-Juan (Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University)
  • Published : 2012.03.31


Background: $FOXP3^+$ regulatory T cells (Tregs) inhibit effector T cell functions and are implicated in tumour progression. However, together with microvessel density (MVD) they remain controversial prognostic predictors for renal cell carcinoma (RCC), and potential associations have yet to be determined. The objective of this study was to determine the prognostic significance of Tregs and MVD and their potential relationship in RCCs. Design: Paraffin-embedded tissues from 62 RCC patients were analysed using immunohistochemistry to detect $FOXP3^+$ lymphocytes, and double immunohistochemistry to detect different microvessel types in the tumour interior, rim and normal kidney tissue, and their correlation with clinicopathological characteristics. Survival analysis was also performed. Results: The presence of $FOXP3^+$ cells in the tumour interior or the rim showed no correlation with death from RCC and other pathological characteristics. Negative correlations were noted between the immature MVD in the tumour interior or the rim and tumour size, tumour stage and overall survival; however, there was no correlation with the nuclear grade or pathological type. A positive correlation between $FOXP3^+$ Tregs and immature MVD (r=0.363, P=0.014) and mature MVD (r=0.383, P=0.009) was confirmed in the tumour interior. However, there was no correlation between $FOXP3^+$ Tregs and mature MVD (r=0.281, P=0.076) or immature MVD (r=0.064, P=0.692) in the tumour rim. Conclusions: In this study, a positive correlation between the presence of $FOXP3^+$ Tregs and immature and mature MVD in RCC was confirmed, which suggests a link between suppression of immunity, tumour angiogenesis and poor prognosis.


  1. Alvaro T, Lejeune M, Salvado MT, et al (2005). Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res, 11, 1467-73.
  2. Bates GJ, Fox SB, Han C, et al (2006). Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol, 24, 5373-80.
  3. Cesana GC, DeRaffele G, Cohen S, et al (2006). Characterization of CD4+CD25+regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol, 24, 1169-77.
  4. Dace DS, Khan AA, Kelly J, Apte RS (2008). Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development. PLoS One, 3, e3381.
  5. Dekel Y, Koren R, Kugel V, Livne PM, Gal R (2002). Significance of angiogenesis and microvascular invasion in renal cell carcinoma. Pathol Oncol Res, 8, 129-32.
  6. Delahunt B, Bethwaite PB, Thornton A (1997). Prognostic significance of microscopic vascularity for clear cell renal cell carcinoma. Br J Urol, 80, 401-4.
  7. Finke JH, Rini B, Ireland J, et al (2008). Sunitinib reverses type- 1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res, 14, 6674-82.
  8. Folkman J (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 1, 27-31.
  9. Fontenot JD, Rudensky AY (2005). A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol, 6, 331-7.
  10. Fuhrman SA, Lasky LC, Limas C (1982). Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol, 6, 655-63.
  11. Gabrilovich D, Ishida T, Oyama T, et al (1998). Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood, 92, 4150-66.
  12. Gaengel K, Genové G, Armulik A, Betsholtz C (2009). Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol, 29, 630-8.
  13. Gerhardt H, Semb H (2008). Pericytes: gatekeepers in tumour cell metastasis? J Mol Med (Berl), 86, 135-44.
  14. Giatromanolaki A, Bates GJ, Koukourakis MI, et al (2008). The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol, 110, 216-21.
  15. Griffiths RW, Elkord E, Gilham DE, et al (2007). Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother, 56, 1743-53.
  16. Gupta S, Joshi K, Wig JD, Arora SK (2007). Intratumoral FOXP3 expression in infiltrating breast carcinoma: Its association with clinicopathologic parameters and angiogenesis. Acta Oncol, 46, 792-7.
  17. Herbst C, Kosmehl H, Stiller KJ, et al (1998). Evaluation of microvessel density by computerized image analysis in human renal cell carcinoma. Correlation to pT category, nuclear grade, proliferative activity and occurrence of metastasis. J Cancer Res Clin Oncol, 124, 141-7.
  18. Hori S, Sakaguchi S (2004). Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect, 6, 745-51.
  19. Kinouchi T, Mano M, Matsuoka I, et al (2003). Immature tumor angiogenesis in high-grade and high-stage renal cell carcinoma. Urology, 62, 765-70.
  20. Kirkali Z, Yorukoglu K, Ozkara E, Kazimoglu H, Mungan U (2001). Proliferative activity, angiogenesis and nuclear morphometry in renal cell carcinoma. Int J Urol, 8, 697-703.
  21. Ko JS, Zea AH, Rini BI, et al (2009). Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res, 15, 2148-57.
  22. Kohler HH, Barth PJ, Siebel A, Gerharz EW, Bittinger A (1996). Quantitative assessment of vascular surface density in renal cell carcinomas. Br J Urol, 77, 650-4.
  23. Li B, Lalani AS, Harding TC, et al (2006). Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res, 12, 6808-16.
  24. Liyanage UK, Moore TT, Joo HG, et al (2002). Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol, 169, 2756-61.
  25. Qian CN, Huang D, Wondergem B, Teh BT (2009). Complexity of tumor vasculature in clear cell renal cell carcinoma. Cancer, 115(10 Suppl), 2282-9.
  26. Sabo E, Boltenko A, Sova Y, et al (2001a). Microscopic analysis and significance of vascular architectural complexity in renal cell carcinoma. Clin Cancer Res, 7, 533-7.
  27. Sabo E, Boltenko A, Sova Y, et al (2001b). Microscopic analysis and significance of vascular architectural complexity in renal cell carcinoma. Clin Cancer Res, 7, 533-7
  28. Seo N, Hayakawa S, Takigawa M, Tokura Y (2001). Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology, 103, 449-57.
  29. Siddiqui SA, Frigola X, Bonne-Annee S, et al (2007). Tumorinfiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res, 13, 2075-81.
  30. Suzuki K, Morita T, Hashimoto S, Tokue A (2001). Thymidine phosphorylase/platelet-derived endothelial cell growth factor (PD-ECGF) associated with prognosis in renal cell carcinoma. Urol Res, 29, 7-12.
  31. Thornton AM, Shevach EM (1998). CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med, 188, 287-96.
  32. Yao X, Qian CN, Zhang ZF, et al (2007). Two distinct types of blood vessels in clear cell renal cell carcinoma have contrasting prognostic implications. Clin Cancer Res, 13, 161-9.
  33. Yildiz E, Ayan S, Goze F, Gokce G, Gultekin EY (2008). Relation of microvessel density with microvascular invasion, metastasis and prognosis in renal cell carcinoma. BJU Int, 101, 758-64.
  34. Yoshino S, Kato M, Okada K (1995). Prognostic significance of microvessel count in low stage renal cell carcinoma. Int J Urol, 2, 156-60.

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