The correlation and prognostic significance of Foxp3 isoform expression in tumor infiltrating lymphocytes and glioma cells from GBM patients

• Main Authors: Jian-Yong Lin, 林建勇
• Other Authors: shao-chih chiu
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/53835870913705937345

碩士 === 中國醫藥大學 === 免疫學研究所碩士班 === 100 === As themost malignant high-grade glioma, prognosis for patients with glioblastoma multiforme (GBM) has only a median survival of 15 month, and 88% mortality within 3 years. Forkhead box protein 3 (Foxp3) is considered to be an important gene for thymically derived and naturally occurring regulatoryTcells (Tregs),whichregulate the immunosuppressive response. Recent studies described the expression of forkhead box P3 (Foxp3) in several tumor cells for providing the possibility of effector T-cell evasion. The present work was to investigate the significance of Foxp3 expression in glioblastoma multiforme (GBM) patients. FOXP3 largely controls the development into Treg cells, and three isoforms Foxp3, Foxp3-WT, FOXP3-△2 and FOXP3-△2△7, have been shown to be expressed in human Treg cells. FOXP3-WT represses NFAT- and NF?羠-mediated gene transcription process , while FOXP3-△2 is involved in repressing the transcriptional activity of the retinoic acid-related orphan receptors alpha (RORα) and gamma-t (RORγt) that regulates the development of antigen-stimulated naive CD4+ T cells into T-helper 17 (Th17) cells . FOXP3-△2△7 has been identified to negatively regulate the function of FOXP3-WT, and FOXP3-△2. We isolated Tregs from infiltrating lymphocytes (TILs) of GBM by FACS analysis. Then, we analyzed the expression of key molecules of Treg function in lymphocytes and tumor cells and correlate with the DC-therapy response of the corresponding patient. Both Tregs and tumor cells express 3 different isoforms of the FOXP3 gene by alternative splicing, one of which represents a naturally occurring dominant negative version of the Foxp3 protein.The proportion of Tregs in CD4+ TILs had been observed the increasing percentage in GBM patients with short survival. However, there was no significant difference in three isoforms of Foxp3 expressed in Tregs comparing with survival of GBM patients. But, three patients with high survival (over 2 years) had shown the expression of dominant negative FOXP3-△2△7 isoform.The differential expression level of Foxp3 isoforms may constitute a potent prognosis factor for GBM patients. Tregs may limit DC-therapy against GBM, while the differential expression of Foxp3 isoforms could provide a basis for the evaluation of the effectiveness of DC-therapy. Functional abrogation of Foxp3 by tuning the splicing preference to its dominant negative isoform may offer an attractive window to inhibit Treg activity.