Science：华人科学家研究成功一种新的肿瘤疫苗

生物谷

     生物谷报道：美国Baylor医学院(BCM)的研究者开发了一种新的肿瘤疫苗，这种基因工程材料可以重新激活肿瘤患者中受到抑制的免疫系统，增强肿瘤特异的免疫反应。结果发表在8月26日的《科学》（Science）杂志上。

        作者来自BCM细胞和基因治疗研究中心的王荣福（Rong-Fu  Wang，音译）教授对这种新的肿瘤治疗策略进行了阐述，肿瘤或感染性疾病中，体内的一种特殊的T淋巴细胞会对免疫反应产生抑制，而新的肿瘤疫苗可以重新激活机体的免疫系统。

        Wang表示：自1995年以来，许多研究者试图研制出一种肿瘤治疗疫苗，经过10年的临床试验，当前存在的问题主要是可以人为诱导机体发生肿瘤特异的免疫反应，但是这种诱导的免疫反应太微弱而且太短暂，不足以根除肿瘤细胞。

        Wang的研究小组先前报道了肿瘤病灶中存在一种肿瘤特异的调节性T淋巴细胞(Treg)，肿瘤细胞可以通过这些T淋巴细胞对自身提供保护。化疗药物或特异性的抗体可以清除这类细胞，但同时也会清除掉机体内具有抗肿瘤功能的淋巴细胞。

        研究者发现一种特异性配体，一种包含鸟嘌呤核苷的DNA物质，可以特异性结合到人类死亡受体8分子上，从而消除了Treg淋巴细胞的免疫抑制效应，使其成为非免疫抑制性T细胞，达到增强抗肿瘤免疫效应的目的。Wang表示：这种肿瘤疫苗马上将进入临床试验阶段，这将对肿瘤或感染性疾病的治疗产生巨大影响。生物谷专家也认为，肿瘤疫苗是近年来国际研究的热点领域，但肿瘤疫苗研制同样是十分困难的，因为科学家们一直无法找到肿瘤细胞的特异性靶点，因此在肿瘤的基因治疗和肿瘤的疫苗研究上存在一定的争论，哪一种才是更有效的肿瘤治疗方法。王博士这一发现，从免疫系统角度入手，成功找到发出了Treg细胞，从而为肿瘤的疫苗研究找到新的突破口。

原文：

Rong-Fu Wang, Xiang Wang, Alicia C. Atwood, Suzanne L. Topalian, and Steven A. Rosenberg。Cloning Genes Encoding MHC Class II-Restricted Antigens: Mutated CDC27 as a Tumor Antigen。

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王博士个人简介：

Professor, Department of Immunology

Professor, The Center for Cell and Gene Therapy

Ph. D., University of Georgia

Postdoctoral fellow, Stanford University

E-mail: rongfuw@bcm.tmc.edu
Research interests: Tumor antigens, cancer vaccine development and the mechanism of self tolerance

Our research interests include the molecular mechanism of T cell mediated tumor immunity and self-tolerance. It is well known that T cells play an important role in the inhibition of tumor growth and tumor destruction. To understand the molecular basis of tumor immunity, we are interested in identifying tumor rejection antigens recognized by CD4+ and CD8+ T cells. Identification of these tumor rejection antigens has provided new opportunities for the development of effective cancer vaccines and for studying the mechanism of T cell mediated tumor immunity and autoimmunity. Specifically, we are currently working on the following projects:

1. Identification of MHC class II-restricted tumor antigens and their role in tumor immunity. In the last few years, a number of MHC class I-restricted tumor antigens have been identified in melanoma and other cancers. Clinical studies using these antigens showed some evidence of therapeutic effect on inhibiting tumor growth, but these immune responses are weak and transient. One possible explanation is that optimal anti-tumor immunity requires the participation of CD4+ and CD8+ T cells since CD4+ T cells play a central role in initiating and maintaining host immune responses against cancer. To this end, we recently developed a novel approach for the identification of MHC class II-restricted tumor antigens recognized by CD4+ T cells. A number of tumor reactive CD4+ T cell lines have been generated. Therefore, we are currently addressing the question of what kinds of tumor antigens are recognized by these CD4+ T cells.

2. Animal tumor models and cancer vaccines. To evaluate the role of MHC class II-restricted tumor antigens and CD4+ T cells, we are investigating CD4+ and CD8+ T cell responses using DR-transgenic mice. Dendritic cells pulsed with peptides or infected with adenovirus encoding tumor antigens are being used to immunize mice. One important aspect of investigation is to understand the mechanism of how to break self-tolerance and direct immune responses against cancer, but not normal tissues. T cell activation and apoptosis are also investigated in animal tumor models. These studies will ultimately lead to the development of more effective cancer vaccinces.

3. The use of microarray technology for the identification Tumor-specific antigens. Although T cell defined tumor antigens have been identified in melanoma and a few other tumors, it has been difficult to tumor reactive T cells thus far. We are using a microarray technology to identify tumor specific antigens in prostate and breast cancers, which are expressed only in tumor cells, but not in normal cells. Their role in tumorigenesis and immunogenecity are being evaluated.

Selected Publications:

Wang, R. F., X. Wang and S. A. Rosenberg. 1999. Identification of a novel MHC class-II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4+ T cells. J. Exp. Med. 189, 1659-1668.
Wang, R. F., X. Wang, A. L. Atwood, S. L. Topalian and S.A. Rosenberg. 1999. Cloning genes encoding MHC class II-restricted antigens: mutated human CDC27 as a tumor antigen. Science 284, 1351-1354.
Zeng, G., C. Touloukian, N. P. Nestifo, S. A. Rosenberg and R. F. Wang. 2000. Identification of CD4+ T cell epitopes from NY-ESO-1 presented by HLA-DR molecules. J. Immunol. 165: 1153-1159
Zeng, G., X. Wang, P. F. Robbins, S.A. Rosenberg, and R.-F. Wang. 2001. Identification of DP4 restricted T cell epitopes from NY-ESO-1: its association with antibody response. PNAS, 98, 3964-3969.
Wang, R.-F and H. Y. Wang. 2002. Enhancement of antitumor immunity by prolonging antigen presentation on dendritic cells. Nature Biotechnology. 20: 149-154.
Wang, H. Y., J. Zhou, K. Zhou, F. M. Marincola, and R. F. Wang. 2002. Identification of a mutated fibronection as a tumor antigen recognized by CD4+ T cells: its role in extracellular matrix formation and tumor metastasis. J. Exp. Med 195: 1397-1406.
Helen Y. Wang, Tihui Fu, Gang Wang, Gang, Zeng, Donna, M. Perry-Lalley, James C. Yang, Nicholas P. Restifo, Patrick Hwu, and R.-F. Wang. 2002. TAT-mediated tumor antigen delivery into dendritic cells for generating CD4+ T cells-dependent antitumor immunity. J. Clinical Investigation 109: 1463-1470
Wang, R.-F. 2002. Novel strategies for enhancing antitumor immunity: intracellular delivery of peptides and identification of MHC class II-restricted tumor antigens. Immunol Reviews 188, 65-80.
Kui Shin Voo, Tihui Fu, Helen Y. Wang, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney, and R.-F. Wang. 2004. Evidence for the presentation of MHC class I-restricted EBNA1 peptides to CD8+ T lymphocytes. J. Exp. Med. 199:1-13.
Helen Y. Wang, Dean A. Lee, Zhong Guo, Guangyong Peng, Hoainam T. Nguyen-Jackson, Ethan M. Shevach and Rong-Fu Wang. 2004. Tumor-specific human CD4+ regulatory T cells and their ligands: implication for immunotherapy. Immunity 20:107-118.
Tihui Fu, Kui Shin Voo and Rong-Fu Wang. 2004. Critical Role of EBNA1-Specific CD4+ T Cells in the Control of Burkitt's Lymphoma in vivo. J. Clinical Investigation, in Press.

For a complete list of Dr. Wang's publications, visit PubMed.