CD4CD25+Foxp3+ Treg and TGF-β play important roles in pathogenesis of Uygur cervical carcinoma

Objective: The aim of the study was to evaluate the function of CD4+CD25+ and Foxp3+ T (Treg) cell and related cytokine in the Uygur patients with cervical carcinoma and CIN (cervical intraepithelial neoplasia). Materials and Methods: 170 Uygur women were recruited in the study from January 2007 to January 2011. The study group was comprised of normal controls, cases of primary cervical carcinoma/CIN, and cervical carcinoma/CIN treated with surgery. The following parameters were examined: clinicopathologic features of patients, percentage of CD4+CD25+Foxp3+ Treg cell in blood and Foxp3 mRNA expression in CD4+CD25 high T cell concentration of serum cytokine. Women with primary cervical carcinoma/CIN after being treated with surgery were compared to the normal controls. Where appropriate, univariate and multivariate analyses were used to identify the function of the Treg and related cytokine. Results: The percentages of CD4+CD25+ Treg were detected as well as in the blood of carcinoma patients and CIN II/III, but the number of cells was much higher compared to both control and CIN I groups (p < 0.01). Moreover, a significant correlation between the expression of Foxp3 mRNA and pathological changes was found. The secretion levels of IL-10, and TGF-beta correlated positively with the process of carcinoma. Furthermore, after surgical operation, the number of Treg cells and related cytokines were decreased. Conclusions: Finally, the authors would like to highlight that CD4+CD25+ Treg, especially the CD4+CD25+Foxp3+ Treg and TGF-beta play important roles in Uygur cervical carcinoma, and may have a correlation with survival. Therefore, the inhibitory function of TGF-beta depletion of Treg cells in combination with other anti-tumor therapies could optimize eradication of malignancies.

Cervical carcinoma; CD4+CD25+Foxp3+ Treg; TGF-β; Uygur

[1] Parkin D.M., Bray F.: “The burden of HPV-related carcinomas”. Vaccine, 2006, 24 (suppl. 3), S11.

[2] Pacholska-Bogalska J., Józefiak A., Nowak W. et al.: “Association of the IGF-I promoter P1 polymorphism with risk of cervical cancer”. Eur. J. Gynaecol. Oncol., 2011, 32, 393.

[3] Barbisan G., Pérez L.O., Difranza L. et al.: “XRCC1 Arg399Gln polymorphism and risk for cervical cancer development in Argentine women”. Eur. J. Gynaecol. Oncol., 2011, 32, 274.

[4] Christian M., Dela G.: “CD4+CD25+Foxp3+ regulatory T cells: from basic research to potential therapeutic use”. Swiss Med. Wkly, 2007, 137, 625.

[5] Bor-Ching S., Wen-Chun C., Ho-Hsiung L., Song-Nan C., Su- Cheng H.: “Immune concept of human papillomaviruses and related antigens in local cancer milieu of human cervical neoplasia”. J. Obstet. Gynaecol., 2007, 33, 103.

[6] Wang R.F.: “Regulatory T cells and innate immune regulation in tumor immunity”. Springer Semin. Immunopathol., 2006, 28, 17.

[7] Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M.: “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 diseases”. J. Immunol., 1995, 155, 1151.

[8] Golghern Jones E., Powrite F. et al.: “Dtpletion of CD25+ regulatory cells Uncovers immune responses to shared murine tumor rejection antigens”. Immunol., 2002, 32, 3267.

[9] Somasundaram R., Jacob L., Swoboda R. et al.: “Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta”. Cancer Res., 2002, 62, 5267.

[10] Wolf A.M., Wolf D., Steurer M. et al.: “Increase of regulatory T cells in the peripheral blood of cancer patients”. Clin. Cancer Res., 2003, 9, 606.

[11] Gallimore A., Sakaguchi S.: “Regulation of tumour immunity by CD25+ T cells”. Immunology, 2002, 107, 5.

[12] Ichihara F., Kono K., Takahashi A., Kawaida H., Sugai H., Fujii H.: “Increased populations of regulatory T cells in peripheral blood and tumor-iniltrating lymphocytes in patients with gastric and esophageal carcinomas”. Clin. Carcinoma Res., 2003, 9, 4404.

[13] Chen M.L., Pittet M.J., Gorelik L. et al.: “Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo”. Proc. Natl. Acad Sci., 2005, 102, 419.

[14] Yan Z., Daoxin M.C., Yong Z. et al.: “The imbalance of Th17/Treg in patients with uterine cervical cancer”. Clinica Chimica Acta, 2011, 412, 894.

[15] Feng L.L., Wang X.: “Targ eting Foxp3+ regulatory T cells-related immunosuppression for cancer immunotherapy”. Chin. Med. J., 2010, 123, 3334.

[16] Kono K., Kawaida H., Takahashi A. et al.: “CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers”. Cancer Immunol. Immunother., 2006, 55, 1064.

[17] Sung K.L., Jee Y.K., Byung W.J. et al.: “Foxp3high and Foxp3low Treg cells differentially correlate with T helper 1 and natural killer cells in peripheral blood”. Hum. Immunol., 2011, 72, 621.

[18] Hori S., Nomura T., Sakaguchi S.: “Control of regulatory T cell development by the transcription factor Foxp3”. Science, 2003, 299, 1057.

[19] Brunkow M.E., Jeffery E.W., Hjerrild K.A. et al.: “Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse”. Nat. Genet., 2001, 27, 68.

[20] Yagi H., Nomura T., Nakamura K. et al.: “Crucial role of FOXP3 in the development and function of human CD4+CD25+ reguzatory T cells”. Int. Immunol., 2004, 16, 1643.

[21] Chen W., J in W., Hardegen N. et al.: “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., 2003, 198, 1875.

[22] Ghiringhelli F., Puig P.E., Roux S. et al.: “Tumor cells convert immature myeloid dendritic cells into TGF-β secreting cells inducing CD4+CD25+ regulatory T cell proliferation”. J. Exp. Med., 202, 919.

[23] Lundqvist A., Palmborg A., Pavlenko M. et al.: “Mature dendritic cells induce tumor specific type 1 regulatory T cells”. J. Immunother., 2005, 28, 229.

[24] Ioppolo S., Notargiacomo S., Profumo E. et al.: “Immunological responses to antigen B from Echinococcus granulosus cyst fluid in hydatid patients”. Parasite Immunol., 1996, 18, 571.

[25] Piccirillo C.A., Letterio J.J., Thornton A.M. et al.: “CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness”. J. Exp. Med., 2002, 196, 237.

[26] Fahlen L., Read S., Gorelik L. et al.: “T cells that cannot respond to TGF-{beta} escape control by CD4+CD25+ regulatory T cells”. J. Exp. Med., 2005, 201, 737.