Baskar S, Ostrand-Rosenberg S, Nabavi N, Nadler L M, Freeman G J, Glimcher L H
Department of Biological Sciences, University of Maryland, Baltimore 21228.
Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5687-90. doi: 10.1073/pnas.90.12.5687.
The inability of the autologous host to reject resident tumor cells is frequently the result of inadequate generation of tumor-specific T cells. Specific activation of T cells occurs after delivery of two signals by the antigen-presenting cell. The first signal is antigen-specific and is the engagement of the T-cell antigen receptor by a specific major histocompatibility complex antigen-peptide complex. For some T cells, the second or costimulatory signal is the interaction of the T-cell CD28 receptor with the B7 activation molecule of the antigen-presenting cell. In the present study, we demonstrate that mouse sarcoma cells genetically engineered to provide both T-cell activation signals stimulate potent tumor-specific CD4+ T cells that cause rejection of both engineered and wild-type neoplastic cells. Two other recent studies have also demonstrated that costimulation via B7 can improve tumor immunity. However, our study differs from these reports by two important observations. (i) One of these studies utilized mouse tumor cells expressing xenogenic viral antigens, and hence, the results are not applicable to wild-type resident tumors. Our study, however, demonstrates that coexpression of B7 by major histocompatibility complex class II+ tumor cells induces immunity in the autologous host that is specific for naturally occurring tumor antigens of poorly immunogenic tumors. (ii) In both earlier studies, only CD8+ T cells were activated after coexpression of B7, whereas in the present report, tumor-specific CD4+ T cells are generated. This report therefore illustrates the role of B7 activation molecule in stimulating potent tumor-specific CD4+ T cells that mediate rejection of wild-type tumors and provides a theoretical basis for immunotherapy of established tumors.
自体宿主无法排斥驻留肿瘤细胞，这通常是肿瘤特异性T细胞生成不足的结果。T细胞的特异性激活发生在抗原呈递细胞传递两个信号之后。第一个信号是抗原特异性的，即特异性主要组织相容性复合体抗原-肽复合物与T细胞抗原受体的结合。对于某些T细胞来说，第二个或共刺激信号是T细胞CD28受体与抗原呈递细胞的B7激活分子之间的相互作用。在本研究中，我们证明经基因工程改造以提供两种T细胞激活信号的小鼠肉瘤细胞可刺激强效的肿瘤特异性CD4+T细胞，这些细胞能导致工程化肿瘤细胞和野生型肿瘤细胞均被排斥。另外两项近期研究也证明，通过B7进行共刺激可增强肿瘤免疫。然而，我们的研究在两个重要方面与这些报告不同。（i）其中一项研究使用了表达异种病毒抗原的小鼠肿瘤细胞，因此，其结果不适用于野生型驻留肿瘤。而我们的研究表明，主要组织相容性复合体II类+肿瘤细胞共表达B7可在自体宿主中诱导针对免疫原性较差肿瘤的天然肿瘤抗原的免疫反应。（ii）在之前的两项研究中，B7共表达后仅激活了CD8+T细胞，而在本报告中，生成了肿瘤特异性CD4+T细胞。因此，本报告阐明了B7激活分子在刺激介导野生型肿瘤排斥的强效肿瘤特异性CD4+T细胞中的作用，并为已形成肿瘤的免疫治疗提供了理论基础。
