口腔鱗狀細胞癌中調節性T細胞及輔助型T細胞-17與臨床病理危險因子之相關性研究

Abstract

在口腔中的惡性腫瘤有九成以上是口腔鱗狀細胞癌，並且是台灣癌症死亡率的第六名，且有逐年增加的趨勢。人類癌症的產生，除了致癌基因突變或是基因的毒性外，目前癌症的免疫編輯也被認為是一個重要的因素之一。本研究假設在口腔鱗狀細胞癌的腫瘤微環境中，是一個不平衡的免疫調節，而影響腫瘤特異性T細胞的免疫作用。FOXP3是調節性T細胞(Tregs)重要的轉錄因子，IL-17是輔助型T 細胞-17 (Th17)的特徵，而B7-H1是一個抑制性的分子。因此，我們調查在人類口腔鱗狀細胞癌中, 腫瘤浸潤性淋巴細胞(TIL)表現FOXP3，IL-17 與B7-H1分子對於此疾病進展可能的關係。本研究利用免疫組織化學染色探討38位口腔鱗狀細胞癌組織中調節性T細胞(Tregs)，輔助型T細胞-17(Th17)及腫瘤浸潤性淋巴細胞(TIL)表現B7-H1的情形，與臨床病理危險因子的相關性。結果顯示，口腔鱗狀細胞癌中浸潤的FOXP3+ 調節性T細胞，IL-17+ TIL及B7-H1+ TIL皆顯著與較差的預後因子有關，如腫瘤的大小 ( p值分別為0.028，0.037，0.043)及病理分期 (p值分別為0.001，0.030，0.002)。利用線性相關性分析及ANOVA發現，浸潤於口腔鱗狀細胞癌組織中的腫瘤浸潤性淋巴細胞表現IL-17與FOXP3+ 調節性T細胞為正相關，並且在統計上有意義 ( p< 0.0001)；此外，浸潤於口腔鱗狀細胞癌組織中的腫瘤浸潤性淋巴細胞表現B7-H1與FOXP3+ 調節性T細胞也是正相關，並且在統計上有意義 ( p< 0.0001)。本研究並觀察到FOXP3+ 調節性T細胞會表現IL-17或B7-H1分子於腫瘤的微環境中。總結來說，口腔鱗狀細胞癌中，FOXP3+ 調節性T細胞及腫瘤浸潤性淋巴細胞表現IL-17或B7-H1分子與患者較差的臨床病理危險因子有關。因此，調節性T細胞與Th17細胞及腫瘤浸潤性淋巴細胞表現B7-H1分子可能在口腔鱗狀細胞癌的腫瘤病理發生過程中扮演重要的角色。

Oral squamous cell carcinoma(OSCC) accounts for over 90% of the oral malignant neoplasms, ranks as the sixth major cause of cancer mortality rate in Taiwan and the incidence rate is raising. In addition to mutation of oncogene and gene toxicity, the cancer immune-editing is one of the important factors in human cancer currently. We proposed that the imbalance of OSCC microenvironment affects immune regulation of cancer specific T-cell immunity. Therefore, we investigated TIL-expressing the FOXP3, a key transcription factor for regulatory T cells (Tregs); IL-17, a hallmark of Th17 cells and B7-H1, an inhibitory molecule in human oral squamous cell carcinoma and their correlation with patients’clinicopathological parameters, by immunohistochemistry staining in 38 OSCC patients. The results revealed that the expression of FOXP3+ Tregs, IL-17+ TIL, and B7-H1+ TIL was significantly associated with tumor size ( p =0.028, 0.037, 0.043, respectively) or pathological stage (p=0.001, 0.030, 0.002, respectively). The linear correction analysis and ANOVA test indicated that FOXP3+ Tregs and IL-17+ TIL were positively correlated (statistically significant, p < 0.0001) and that positive correction was also found between FOXP3+ Tregs and B7-H1+ TIL (statistically significant, p< 0.0001). Furthermore, we also observe the expression of IL-17 or B7-H1 molecules on FOXP3+ Tregs in the tumor microenvironment. Therefore, FOXP3+ Tregs , IL-17+ TIL and B7-H1+ TIL were associated with poor prognostic factors. Consequently, TIL-expressing the FOXP3, IL-17 and B7-H1 may play an important role in the tumor pathogenesis of oral squamous cell carcinoma.