近日國際著名的《臨床腫瘤雜志》發(fā)表了復旦大學附屬中山醫(yī)院肝癌研究所樊嘉教授和邱雙健副教授指導二年級博士研究生高強完成的關于肝癌免疫微環(huán)境與預后的文章,，標志著我國肝癌臨床研究取得重大突破。
《臨床腫瘤雜志》 （Journal of Clinical Oncology）是美國臨床腫瘤學會 （ASCO,，American Society of Clinical Oncology）主辦的官方雜志,，主要介紹國際臨床腫瘤領域的最新進展和研究成果,。在剛剛發(fā)布的2006年所有6100多種SCI收錄雜志中影響因子（IF, impact factor）位列第63，高達13.60分,，為國際一流的著名期刊,。該文立足于大量的臨床實踐，借助先進的組織芯片技術（組織芯片由上海生物芯片－上海芯超生物科技有限公司制作）,，瞄準國際腫瘤學研究的最新進展，以探索臨床現(xiàn)象,、揭示臨床規(guī)律為目標,。既往在此領域的研究僅僅提示了肝癌患者體內(nèi)可能存在一種新型的抑制性T淋巴細胞——調(diào)節(jié)性T淋巴細胞增多的現(xiàn)象，這種抑制性T淋巴細胞的存在大大降低了機體抗腫瘤免疫效應的發(fā)揮,，但缺少有力的證據(jù),，對其臨床意義也不是太清楚。此次研究從腫瘤免疫微環(huán)境入手,，對肝癌局部免疫細胞類型,、數(shù)目、部位及其功能狀態(tài)與肝癌門靜脈癌栓形成等臨床病理特征以及預后的關系進行了深入,、系統(tǒng)的研究,，發(fā)現(xiàn)肝癌局部免疫狀態(tài)，特別是微環(huán)境中的調(diào)節(jié)性T淋巴細胞及其與殺傷性T淋巴細胞的力量對比關系與門靜脈癌栓形成,、轉移復發(fā)密切相關,。當殺傷細胞增多時，可以有效地對抗調(diào)節(jié)性T細胞對患者免疫系統(tǒng)的抑制作用,，能夠增強機體的免疫力,，有利于殺傷腫瘤細胞。因此通過適當?shù)拿庖哒{(diào)節(jié)對降低肝癌術后復發(fā)轉移,、進一步提高患者療效具有極其重要意義,。復旦大學附屬中山醫(yī)院的這項成果引起了國際學術界的高度重視和極大興趣，《臨床腫瘤雜志》專門為此文配發(fā)編者按,，指出這篇論文的發(fā)表進一步明確了機體抗瘤免疫反應的核心環(huán)節(jié)與機制,，對于篩選肝癌術后復發(fā)的高危患者,、選擇正確的術后治療手段和免疫治療措施具有重要指導價值,。有望通過進一步的臨床驗證找到有效的預防肝癌術后復發(fā)轉移的新手段和途徑。
以我國著名的肝臟外科專家,、復旦大學附屬中山醫(yī)院副院長樊嘉教授為首的肝癌研究所“微環(huán)境與肝癌轉移復發(fā)”課題組自2003年起即致力于“宿主與腫瘤”相互作用的探索,，是國內(nèi)最早系統(tǒng)開展相關研究的單位之一。這篇論文的發(fā)表也標志著該課題組取得了重要的階段性成果,，目前基于此項研究的一項臨床隨機對照研究以及一系列基礎研究正在有條不穩(wěn),、深入地進行,。
這篇論文是我國近年來發(fā)表的臨床研究領域極少數(shù)高影響因子（大于10分）論文之一，也是中山醫(yī)院歷史上研究生在導師的指導下完全立足于醫(yī)院自身,、具有全部知識產(chǎn)權的影響因子最高的論文,。論文的發(fā)表標志著我國腫瘤臨床研究取得了重大突破、進一步確立了我國肝癌研究的國際領先地位,；也是中山醫(yī)院科研體制創(chuàng)新,、研究生教育機制創(chuàng)新的重要成果，對于進一步基于我國大量的臨床資料基礎上深入探索臨床現(xiàn)象,、揭示臨床規(guī)律,、早日征服肝癌具有重要意義。
原始出處：
Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2586-2593
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.09.4565
Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection
Qiang Gao, Shuang-Jian Qiu, Jia Fan, Jian Zhou, Xiao-Ying Wang, Yong-Sheng Xiao, Yang Xu, Yi-Wei Li, Zhao-You Tang
From the Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, the Chinese Ministry of Education, Shanghai, People's Republic of China
Address reprint requests to Jia Fan, MD, PhD, Liver Cancer Institute, Fudan University, 136 Yi Xue Yuan Rd, Shanghai 200032, People's Republic of China; e-mail: [email protected]
Purpose: To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection.
Patients and Methods: CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff.
Results: CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031).
Conclusion: Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
Supported by grants from the National Natural Science Foundation of China (Grant No. 30200268) and the Foundation of China National "211" Project for Higher Education.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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