近日國(guó)際著名的《臨床腫瘤雜志》發(fā)表了復(fù)旦大學(xué)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(dǎo)二年級(jí)博士研究生高強(qiáng)完成的關(guān)于肝癌免疫微環(huán)境與預(yù)后的文章,，標(biāo)志著我國(guó)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(guó)臨床腫瘤學(xué)會(huì) （ASCO,，American Society of Clinical Oncology）主辦的官方雜志,，主要介紹國(guó)際臨床腫瘤領(lǐng)域的最新進(jìn)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(dá)13.60分,，為國(guó)際一流的著名期刊。該文立足于大量的臨床實(shí)踐,，借助先進(jìn)的組織芯片技術(shù)（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(zhǔn)國(guó)際腫瘤學(xué)研究的最新進(jìn)展，以探索臨床現(xiàn)象、揭示臨床規(guī)律為目標(biāo),。既往在此領(lǐng)域的研究?jī)H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(xì)胞——調(diào)節(jié)性T淋巴細(xì)胞增多的現(xiàn)象,，這種抑制性T淋巴細(xì)胞的存在大大降低了機(jī)體抗腫瘤免疫效應(yīng)的發(fā)揮，但缺少有力的證據(jù),，對(duì)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(duì)肝癌局部免疫細(xì)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(yù)后的關(guān)系進(jìn)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(xì)胞及其與殺傷性T淋巴細(xì)胞的力量對(duì)比關(guān)系與門靜脈癌栓形成、轉(zhuǎn)移復(fù)發(fā)密切相關(guān),。當(dāng)殺傷細(xì)胞增多時(shí),，可以有效地對(duì)抗調(diào)節(jié)性T細(xì)胞對(duì)患者免疫系統(tǒng)的抑制作用，能夠增強(qiáng)機(jī)體的免疫力,，有利于殺傷腫瘤細(xì)胞,。因此通過(guò)適當(dāng)?shù)拿庖哒{(diào)節(jié)對(duì)降低肝癌術(shù)后復(fù)發(fā)轉(zhuǎn)移、進(jìn)一步提高患者療效具有極其重要意義,。復(fù)旦大學(xué)附屬中山醫(yī)院的這項(xiàng)成果引起了國(guó)際學(xué)術(shù)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(jìn)一步明確了機(jī)體抗瘤免疫反應(yīng)的核心環(huán)節(jié)與機(jī)制,，對(duì)于篩選肝癌術(shù)后復(fù)發(fā)的高?；颊摺⑦x擇正確的術(shù)后治療手段和免疫治療措施具有重要指導(dǎo)價(jià)值,。有望通過(guò)進(jìn)一步的臨床驗(yàn)證找到有效的預(yù)防肝癌術(shù)后復(fù)發(fā)轉(zhuǎn)移的新手段和途徑,。
以我國(guó)著名的肝臟外科專家、復(fù)旦大學(xué)附屬中山醫(yī)院副院長(zhǎng)樊嘉教授為首的肝癌研究所“微環(huán)境與肝癌轉(zhuǎn)移復(fù)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(guó)內(nèi)最早系統(tǒng)開(kāi)展相關(guān)研究的單位之一,。這篇論文的發(fā)表也標(biāo)志著該課題組取得了重要的階段性成果，目前基于此項(xiàng)研究的一項(xiàng)臨床隨機(jī)對(duì)照研究以及一系列基礎(chǔ)研究正在有條不穩(wěn),、深入地進(jìn)行,。
這篇論文是我國(guó)近年來(lái)發(fā)表的臨床研究領(lǐng)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(dǎo)師的指導(dǎo)下完全立足于醫(yī)院自身,、具有全部知識(shí)產(chǎn)權(quán)的影響因子最高的論文,。論文的發(fā)表標(biāo)志著我國(guó)腫瘤臨床研究取得了重大突破、進(jìn)一步確立了我國(guó)肝癌研究的國(guó)際領(lǐng)先地位,；也是中山醫(yī)院科研體制創(chuàng)新,、研究生教育機(jī)制創(chuàng)新的重要成果,，對(duì)于進(jìn)一步基于我國(guó)大量的臨床資料基礎(chǔ)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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