"Indoleamine 2,3-Dioxygenase及Interferon-gamma於口腔鱗狀細胞癌中之表現"

Abstract

背景 Indoleamine 2,3-Dioxygenase（IDO）為控管人體中Tryptophan（Trp）代謝重要酵素，藉由促進其代謝，產生抑制T cell的活性及加速T cell凋亡的效果，以達免疫抑制之功效。在正常的生理狀態下，IDO常表現於母體的胎盤內，做為抑制免疫的角色以避免同種異體的胎兒遭受母體免疫系統的攻擊。在惡性腫瘤中，受到了Interferon-gamma（IFN﹣γ）刺激，IDO的大量表現扮演了幫助腫瘤細胞脫逃出免疫系統的監控與攻擊的角色（immune escape），在人體癌症中如大腸癌、膀胱癌及乳癌等，其表現量都有提高的情形，且與腫瘤的分期（stage）甚至癒後（prognosis）都有顯著的相關性。本研究欲探討IDO與IFN﹣γ於口腔鱗狀細胞癌（OSCC）之病理組織中的表現量，並且分析其臨床各參數和存活時間之關係。 材料與方法 本研究目的在於探討IDO與IFN﹣γ於62例OSCC中的表現，藉由免疫組織化學染色方法，並以陽性染色指標Labeling index（LI）記錄其染色程度。利用Student T test及ANOVA分析其平均值差異；點二系列相關（point-biserial correlation）、皮爾森相關（Pearson correlation）、斯皮爾曼相關（Spearman correlation）分析其相關性；Linear regression分析IDO和IFN﹣γ之因果關係；Cox proportional hazard regression model及Kaplan-Meier 存活率方法來分析口腔鱗狀細胞癌患者臨床病理參數及存活率與IDO及IFN﹣γ的表現之相關性，並分析是否有影響存活時間的獨立預後因子。 結果 在口腔鱗狀細胞癌的組織中，IDO的平均陽性標記指數為27.26%，IFN﹣γ的平均陽性標記指數為55.81%；其中IDO高表現（LI≥40）的樣本佔所有樣本之27.12﹪，IFN﹣γ（LI≥40）高表現的樣本佔所有樣本之79.66%。二者陽性標記指數有顯著相關性（p=0.001），相關係數為0.41，R square為0.17。 IDO的陽性標記指數與腫瘤的大小（T status）及腫瘤分期（stage）有顯著相關（p=0.22）（p=0.05）。在邊緣侵犯的腫瘤中，IFN﹣γ的表現量與未侵犯的組別相比有顯著的增加，且有表現量與侵犯與否有相關性；而與周邊淋巴血管侵犯與否有相關性。 其餘各項臨床參數中，都與IDO和IFN﹣γ之表現沒有顯著相關性。在單變量之Cox proportional hazard regression model中，IDO之陽性標記指數，淋巴結轉移分期（N status）及腫瘤分化（differentiation）為顯著存活因子。在多變量之Cox proportional hazard regression model中，僅淋巴結轉移分期（N status）為其顯著存活因子。 在Kaplan-Meier plots中，IDO陽性染色指標顯著地縮短病人之總存活時間（overall survival），Log-Rank Test之p值為 0.037。IFN﹣γ陽性染色指標則有縮短病人總存活時間之趨勢，但未達統計意義。 結論 於本研究中，IN﹣γ的陽性染色指標與IDO的陽性染色指標有顯著關聯性。IDO的陽性染色指標與腫瘤大小及口腔癌分期有顯著關聯性，且與口腔細胞癌患者的存活時間有關。在口腔癌患者中，IDO的表現量較高者其存活時間較短。

Background Indoleamine 2,3-Dioxygenase（IDO）regulates the catabolism of Tryptophan（Trp） and suppresses T cells proliferation and enhances T cells apoptosis by consuming Trp. In normal physical status, IDO expresses in planceta preventing allogenic fetal rejection by catabolism of Trp. Expression of IDO in malignant tumor, elevated by the effect of IFN-γ, plays an important role in the mechanism of the immune escape which is the cell extrinsic traits of cancers. Many researches reveal increasing IDO level in malignant tumor, including colon cancer, bladder cancer and breast cancer, etc., related to the advanced stage and poor prognosis. The emphasis of this study is on the expressions of IDO and IFN-γ in pathological specimens from oral squamous cell carcinoma（OSCC）and the correlation between these expressions, clinical and pathologic parameters, and the survival time. Materials and Methods The goal in this study is examining the expression of IDO and IFN-γ in 62 specimens diagnosed as OSCC by immunohistochemistry（IHC） staining and recording the grade of positive staining as labeling index（LI）. The correlations between the expression of IDO and IFN-γ, clinical and pathological parameter, the disease-free survival and overall survival were analyzed via student T test, ANOVA, linear regression, correlation analysis, including point-biserial correlation, Pearson correlation, Spearman correlation, Survival analysis, including Cox proportional hazard regression model and Kaplan-Meier plots. Results The average labeling index of IDO in OSCC specimens is 27.26%, and the average labeling index of IFN-Υ is 55.81%. The rate of specimens with high-IDO expression （LI≥40） in all OSCC specimens is 27.12% and the rate of the specimens with high-IFN-γ expression is 79.66%. The expressions of IDO and IFN-γ have significant correlation between each over （p=0.001）, R=0.41 The labeling index of IDO has significant correlation between T status and tumor stage （p=0.22） （p=0.05）. In the group with marginal involvement, the labeling index of IFN-γ is elevated significantly and there is a significant correlation between marginal involvement and LI of IFN-γ. The correlation between lymphovascular invasion and LI of IFN-γ is significant too. There is no correlation between the other clinical parameters and the expression of IDO and IFN-γ. In univariate Cox proportional hazard regression model, LI of IDO, N status and tumor differentiation are statistically significant. In multivariate Cox proportional hazard regression model, only N status is significant. Kaplan-Meier survival analysis showed that patients had shorter overall survival time with high LI of IDO. The Log-Rank Test p value is 0.037. High LI of IFN-γ indicates the tendency of decreasing overall survival time in OSCC patients, but is not statistically significant. Conclusions The labeling index of IDO has significant correlation with the labeling index of IFN-γ, T status of tumor, and tumor stage. In OSCC patients, high expression of IDO indicates shorter overall survival. IDO and IFN-γ may have influence on each other and indicate advanced tumor stage and poor prognosis.