調節性T細胞與介白素-1β、介白素-6以及變形生長因子-β於口腔鱗狀上皮細胞癌之表現

Regulatory T Cells and the Expression of Interleukin-1β, Interleukin-6 and Transforming Growth Factor-β in Oral Squamous Cell Carcinoma

唐宗凡(Tzung-Fan Tang)

指導教授 ： 賈景山

共同指導教授 ： 李正喆(Jang-Jaer Lee)

國立臺灣大學/牙醫專業學院/臨床牙醫學研究所/碩士(2010年)

https://doi.org/10.6342/NTU.2010.02546

摘要

背景：口腔鱗狀上皮細胞癌(oral squamous cell carcinoma, OSCC)的發生以及生長與發炎反應有很高的相關性，而發炎反應則是由介白素-1β(interleukin-1β, IL-1β)以及介白素-6(interleukin-6, IL-6)等促發炎反應的細胞激素來調控。然而在腫瘤的微環境中適應性免疫細胞卻是被抑制的。調節性T細胞(regulatory T cell, Treg)的功能主要是藉由變形生長因子(Transforming growth factor-β, TGF-β)等細胞激素的調控，對免疫系統造成抑制。調節性T細胞的抗發炎能力，或許有助於腫瘤的控制，然而也有可能幫助腫瘤逃離免疫系統的監測，進而幫助腫瘤的生長。因此本研究欲觀察，能產生抗發炎反應的Treg細胞以及TGF-β，與能促進發炎反應的IL-1β以及IL-6於OSCC中的表現，以及其與臨床以及組織病理上各項參數之相關性。
材料與方法：本研究利用免疫組織化學染色方法，觀察Foxp3、TGF-β、IL-1β以及IL-6於71例於1999年至2004年間於台大口腔顎面外科接受手術切除治療之OSCC患者組織中的表現。並分別評估Foxp3、TGF-β、IL-1β以及IL-6於OSCC腫瘤細胞以及基質中的表現。Foxp3、TGF-β、IL-1β以及IL-6於OSCC中之表現與各項臨床與病理之參數的關係，則使用Pearson product-moment correlation coefficient、Student’s t test、Kruskal-Wallis H test以及Mann-Whitney U test來評估。Foxp3、TGF-β、IL-1β以及IL-6於OSCC中之表現與患者存活之關係則使用Kaplan-Meier survival analysis來評估。
結果：所有的病例皆表現Foxp3以及IL-6，而IL-1β以及TGF-β則各有一個病例未表現。Foxp3、TGF-β、IL-1β以及IL-6之各項表現於彼此之間或是細胞激素本身互有相關性。於早期的腫瘤中Foxp3的表現量較晚期腫瘤為高，而晚期的腫瘤中IL-1β於腫瘤細胞中表現則較早期為高。此外，TGF-β於超過50%的腫瘤細胞中表現則患者的累積存活率越好。
結論：OSCC是一高度發炎的腫瘤，IL-1β於較具侵犯性的腫瘤之腫瘤細胞中表現較高，Foxp3則於較早期的腫瘤細胞表現較高。具有菸酒檳榔等不良習慣的患者，IL-1β於腫瘤細胞中，而IL-6於腫瘤基質中的表現較高，但Treg的表現較低，使腫瘤偏向發炎的環境。另外，TGF-β於腫瘤中表現超過50%腫瘤細胞，則累積存活率較高，表示TGF-β對OSCC的預後是有幫助的。於本研究中，Foxp3、IL-1β以及IL-6對於OSCC的存活率以及預後是沒有影響的。

關鍵字

調節性T細胞 ； 介白素-1β ； 介白素-6 ； 變形生長因子-β ； 口腔鱗狀上皮細胞癌

並列摘要

Background: The occurrence and progression of oral squamous cell carcinoma (OSCC) are highly correlated with inflammation, which is mediated by pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6). But the adaptive immune cells are suppressed in the tumor microenvironment. Regulatory T cells (Tregs) suppress immune response through transforming growth factor-β (TGF-β) mediation. Tregs may suppress inflammatory response and help the control of tumor, but also may support tumor to escape from immune surveillance and promote tumor progression. The study was to investigate the expression of Treg and TGF-β, which exert anti-inflammation, and IL-1β and IL-6, which promote inflammatory response in OSCC and their associations with clinical and pathological features.
Materials and methods: Surgical specimens from 71 patients treated for OSCC at Department of Oral and Maxillofacial Surgery, National Taiwan university hospital, were evaluated for Foxp3, TGF-β, IL-1β and IL-6 expression by immunihistochemical staining. The expression of Foxp3, TGF-β, IL-1β and IL-6 in OSCC cancer and stromal cells were evaluated respectively. Associations of Foxp3, TGF-β, IL-1β and IL-6 expression with clinical and pathological features were evaluated by using Pearson product-moment correlation coefficient, Student’s t test, Kruskal-Wallis H test and Mann-Whitney U test. Associations of Foxp3, TGF-β, IL-1β and IL-6 expression with survival of patients from OSCC were evaluated by using Kaplan-Meier survival analysis.
Results: All patients showed Foxp3 and IL-6 expression. IL-1β and TGF-β have one case didn’t show any positive expression in tumor and stromal cells respectively. The expression of Foxp3, TGF-β, IL-1β and IL-6 were correlated with themselves or each others. Compared early stage with advanced stage tumor, the expression of Foxp3 was higher in early stage, and the expression of IL-1β in tumor cells was higher in advanced stage. The higher expression of TGF-β in tumor cells was associated with better cumulative proportion surviving.
Conclusions：OSCC is a highly associated with inflammatory response, and the expression of IL-1β was higher in more invasively tumor, and Foxp3 expression was higher in early stage tumor. If the patients had smoking and/or alcohol drinking and/or betel quid chewing, the expression of IL-1β was higher in cancer cells and IL-6 was higher in stromal cells, but the amount of Tregs were lower. This result indicates that these habits deviate tumor to more inflammatory microenvironment. If over 50% tumor cells express TGF-β, the cumulative proportion surviving would be higher, indicating TGF-β associated with better prognosis. In this study, the expression of Foxp3, IL-1β, IL-6 have no impact on the survival and prognosis of OSCC.

並列關鍵字

Regulatory T Cell ； Interleukin-1β ； Interleukin-6 ； Transforming Growth Factor-β ； Oral Squamous Cell Carcinoma

參考文獻

Abe M, Kondo S, Hirano S, Ambo Y, Tanaka E, Morikawa T, Okushiba S, and Katoh H. 2003. Long-term survival after radical resection of advanced pancreatic cancer: a case report with special reference to CD8+ T-cell infiltration. Int J Gastrointest Cancer 33(2-3):107-110.

Achen MG, McColl BK, and Stacker SA. 2005. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7(2):121-127.

Achur RN, Freeman WM, and Vrana KE. 2010. Circulating cytokines as biomarkers of alcohol abuse and alcoholism. J Neuroimmune Pharmacol 5(1):83-91.

Ahn JM, Huang CC, and Cho HT. 1993. Localization of interleukin-1 in human squamous carcinomas of the head and neck. Laryngoscope 103(5):529-532.

Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J, Banham AH, Roncador G, Montalban C, and Piris MA. 2005. Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11(4):1467-1473.