B7-CD28/CTLA-4 INTERACTIONS IN IMMUNITY TO TUMORS

描述(改编自《调查者摘要》)：研究内容如下 建议阐明B7/CD28的生理功能 共刺激通路在T细胞依赖获得中的作用 迄今免疫抑制的小鼠荷瘤小鼠的肿瘤清除免疫 肿瘤和广泛的转移。我们将特别强调 确定B7-1和/或B7-2是否上调宿主细胞或肿瘤的表达 细胞在小剂量马法兰诱导的肿瘤获取中起重要作用 消除MOPC-315肿瘤载体的免疫。此外，这项研究 将阐明低剂量化疗导致 上调B7-1和/或B7-2的表达 小剂量L-PAM诱导的肿瘤清除作用 迄今免疫抑制的MOPC-315肿瘤携带者的免疫。研究 也被建议用来确定为什么阻止B7/CTLA-4相互作用 不会为MOPC-315肿瘤携带者提供任何治疗益处。 具体地说，它将检验这样一个假设，即抗CTLA-4的失败 在MOPC-315肿瘤系统中提供任何治疗益处的治疗方法是 由于在反CTLA-4管理的时候， 活化的T细胞不是主要参与的类型 产生/发挥(而不是抑制)肿瘤根除免疫， 抗CTLA-4治疗可阻止两者活性的关闭 激活的T细胞的种类。此外，还将确定是否 抗CTLA-4治疗的有益效果可以在MOPC-315中实现 当平衡通过外部操作改变时，肿瘤系统， 向激活的T细胞转化，参与产生/发挥 消除肿瘤的免疫力。最后，将确定是否 从MOPC-315肿瘤模型中学到的原理可以扩展到 不同的肿瘤模型。总括而言，拟议的研究将提供 有关细胞生理功能的有价值的信息 B7-CD28/CTLA-4共刺激通路在荷瘤小鼠体内的表达 在小鼠接受已知的治疗方式之前和之后 导致迄今为止的人获得肿瘤根除免疫 免疫抑制肿瘤携带者。这些信息将反过来促进 设计合理的方法来操纵这一关键的免疫调节 使肿瘤携带者受益的途径。

DESCRIPTION (Adapted from the Investigator's Abstract): Studies are proposed to elucidate the physiological function of the B7/CD28 costimulatory pathway in the acquisition of T-cell-dependent tumor-eradicating immunity by hitherto immunosuppressed mice bearing large tumors and extensive metastases. Particular emphasis will be placed on determining if B7-1 and/or B7-2 up-regulation on host cells or on tumor cells is important for the low-dose melphalan-induced acquisition of tumor eradicating immunity by MOPC-315 tumor bearers. In addition, this study will elucidate the mechanisms through which the low-dose chemotherapy leads to up-regulation of B7-1 and/or B7-2 expression by cells identified as important for the low-dose L-PAM-induced acquisition of tumor-eradicating immunity by the hitherto immunosuppressed MOPC-315 tumor bearers. Studies are also proposed to determine why blockade of the B7/CTLA-4 interaction does not offer any therapeutic benefits to MOPC-315 tumor bearers. Specifically, it will test the hypothesis that the failure of anti-CTLA-4 treatment to offer any therapeutic benefits in the MOPC-315 tumor system, is due to the fact that at the time of anti-CTLA-4 administration, the activated T-cells are not predominantly of the type that is involved in the generation/exertion (rather than inhibition) of tumor-eradicating immunity, and the anti-CTLA-4 treatment prevents the shut-off of the activity of both kinds of activated T-cells. In addition, it will be determined if the beneficial effects of anti-CTLA-4 treatment can be realized in the MOPC-315 tumor system when the balance is shifted through external manipulations, towards activated T-cells that are involved in the generation/exertion of tumor-eradicating immunity. Finally, it will be determined if the principles learned from the MOPC-315 tumor model can be extended to a different tumor model. In summary, the studies proposed will provide valuable information regarding the physiological functions of the B7-Cd28/CTLA-4 costimulatory pathway in vivo in mice bearing a large tumor, both before and after the mice are subjected to therapeutic modalities known to lead to the acquisition of tumor-eradicating immunity by the hitherto immunosuppressed tumor bearers. This information will in turn facilitate the design of rational approaches to manipulate this key immunoregulatory pathway to the benefit of the tumor bearers.