近日国际著名的《临床肿瘤杂志》发表了复旦大学附属中山医院肝癌研究所樊嘉教授和邱双健副教授指导二年级博士研究生高强完成的关于肝癌免疫微环境与预后的文章，标志着我国肝癌临床研究取得重大突破。
《临床肿瘤杂志》 （Journal of Clinical Oncology）是美国临床肿瘤学会 （ASCO，American Society of Clinical Oncology）主办的官方杂志，主要介绍国际临床肿瘤领域的最新进展和研究成果。在刚刚发布的2006年所有6100多种SCI收录杂志中影响因子（IF, impact factor）位列第63，高达13.60分，为国际一流的著名期刊。该文立足于大量的临床实践，借助先进的组织芯片技术（组织芯片由上海生物芯片－上海芯超生物科技有限公司制作），瞄准国际肿瘤学研究的最新进展，以探索临床现象、揭示临床规律为目标。既往在此领域的研究仅仅提示了肝癌患者体内可能存在一种新型的抑制性T淋巴细胞——调节性T淋巴细胞增多的现象，这种抑制性T淋巴细胞的存在大大降低了机体抗肿瘤免疫效应的发挥，但缺少有力的证据，对其临床意义也不是太清楚。此次研究从肿瘤免疫微环境入手，对肝癌局部免疫细胞类型、数目、部位及其功能状态与肝癌门静脉癌栓形成等临床病理特征以及预后的关系进行了深入、系统的研究，发现肝癌局部免疫状态，特别是微环境中的调节性T淋巴细胞及其与杀伤性T淋巴细胞的力量对比关系与门静脉癌栓形成、转移复发密切相关。当杀伤细胞增多时，可以有效地对抗调节性T细胞对患者免疫系统的抑制作用，能够增强机体的免疫力，有利于杀伤肿瘤细胞。因此通过适当的免疫调节对降低肝癌术后复发转移、进一步提高患者疗效具有极其重要意义。复旦大学附属中山医院的这项成果引起了国际学术界的高度重视和极大兴趣，《临床肿瘤杂志》专门为此文配发编者按，指出这篇论文的发表进一步明确了机体抗瘤免疫反应的核心环节与机制，对于筛选肝癌术后复发的高危患者、选择正确的术后治疗手段和免疫治疗措施具有重要指导价值。有望通过进一步的临床验证找到有效的预防肝癌术后复发转移的新手段和途径。
以我国著名的肝脏外科专家、复旦大学附属中山医院副院长樊嘉教授为首的肝癌研究所“微环境与肝癌转移复发”课题组自2003年起即致力于“宿主与肿瘤”相互作用的探索，是国内最早系统开展相关研究的单位之一。这篇论文的发表也标志着该课题组取得了重要的阶段性成果，目前基于此项研究的一项临床随机对照研究以及一系列基础研究正在有条不稳、深入地进行。
这篇论文是我国近年来发表的临床研究领域极少数高影响因子（大于10分）论文之一，也是中山医院历史上研究生在导师的指导下完全立足于医院自身、具有全部知识产权的影响因子最高的论文。论文的发表标志着我国肿瘤临床研究取得了重大突破、进一步确立了我国肝癌研究的国际领先地位；也是中山医院科研体制创新、研究生教育机制创新的重要成果，对于进一步基于我国大量的临床资料基础上深入探索临床现象、揭示临床规律、早日征服肝癌具有重要意义。
原始出处：
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: jiafan99@yahoo.com
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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