Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer
Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer
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DOI：
10.1073/pnas.94.15.8099
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发表时间：
1997-07-22
影响因子：
11.1
通讯作者：
Allison, JP
中科院分区：
文献类型：
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作者：
Kwon, ED;Hurwitz, AA;Allison, JP
由于缺乏针对前列腺癌的相关动物研究模型，确定潜在有用的基于免疫的前列腺癌治疗方法受到严重限制。此外，一些参与完全和适当的抗肿瘤T细胞激活的最关键机制直到最近才被确定为实验操作，即参与T细胞激活共刺激途径的成分，因此，我们建立了一种新的同基因小鼠前列腺癌模型，该模型允许我们研究两种不同的操作方法，旨在通过增强T细胞共刺激引发抗前列腺癌反应：(i)通过前列腺癌细胞转导表达B7.1配体提供直接共刺激；（ii）体内抗体介导的T细胞CTLA-4阻断，阻止T细胞下调。在本研究中，我们发现来自转基因小鼠的致瘤性前列腺癌细胞系TRAMPC1 （pTC1）在表达共刺激配体B7.1后，可被同源C57BL/6小鼠排斥，而胸腺小鼠不排斥。此外，我们还证明了体内抗体介导的CTLA-4阻断可增强抗前列腺癌的免疫反应。抗ctla -4引起的反应范围从野生型pTC1生长的显著减少到这些细胞的完全排斥。总之，这些实验表明，适当操纵T细胞共刺激和抑制信号可能为前列腺癌免疫治疗提供基础和高度适应性的基础。我们介绍的同基因小鼠模型为进一步测试前列腺癌的免疫治疗提供了一个全面的系统。
The identification of potentially useful immune-based treatments for prostate cancer has been severely constrained by the scarcity of relevant animal research models for this disease, Moreover, some of the most critical mechanisms involved in complete and proper antitumoral T cell activation have only recently been identified for experimental manipulation, namely, components involved in the costimulatory pathway for T cell activation, Thus, we have established a novel syngeneic murine prostate cancer model that permits us to examine two distinct manipulations intended to elicit an antiprostate cancer response through enhanced T cell costimulation: (i) provision of direct costimulation by prostate cancer cells transduced to express the B7.1 ligand and (ii) in vivo antibody-mediated blockade of the T cell CTLA-4, which prevents T cell down-regulation. In the present study we found that a tumorigenic prostate cancer cell line, TRAMPC1 (pTC1), derived from transgenic mice, is rejected by syngeneic C57BL/6 mice, but not athymic mice, after this cell line is transduced to express the costimulatory ligand B7.1, Also, we demonstrated that in vivo antibody-mediated blockade of CTLA-4 enhances antiprostate cancer immune responses, The response raised by anti-CTLA-4 administration ranges from marked reductions in wild-type pTC1 growth to complete rejection of these cells, Collectively, these experiments suggest that appropriate manipulation of T cell costimulatory and inhibitory signals may provide a fundamental and highly adaptable basis for prostate cancer immunotherapy, Additionally, the syngeneic murine model that we introduce provides a comprehensive system for further testing of immune-based treatments for prostate cancer.