T-Cell Independent Antitumor Mechanisms of CD40 Ligation

在一些鼠肿瘤模型中，通过其CD 40受体刺激抗原呈递细胞可诱导抗肿瘤T细胞应答。 我们最近发现，即使在T细胞不存在的情况下，激动性抗CD 40 mAb也可以通过激活自然杀伤（NK）细胞诱导抗肿瘤作用。 我们的初步结果表明，通过CD 40连接激活的巨噬细胞也可以在体内杀死肿瘤细胞。 我们还假设，当分别与设计用于激活抗肿瘤T细胞（肿瘤疫苗）或NK细胞（免疫细胞因子融合蛋白）的免疫抑制剂组合时，通过CD 40连接激活的T细胞或NK细胞将引起增强的抗肿瘤破坏。 本项目的目的是确定抗CD 40 mAb治疗诱导T细胞依赖性或T细胞非依赖性抗肿瘤效应的机制，鉴定参与这些应答的特异性细胞和细胞因子，并评价抗CD 40 mAb与其他形式的免疫治疗联合使用时的辅助抗肿瘤疗效。具体而言，我们将通过以下三个目标来实现这一目标：1.确定抗CD 40 mAb优先激活T细胞或NK细胞的机制。2.评价抗CD 40 mAb诱导的NK细胞和巨噬细胞介导的抗肿瘤作用机制。3.确定抗CD 40 mAb在增强免疫疗法对免疫原性差的肿瘤的作用。 总之，这些研究将表征抗CD 40 mAb诱导的抗肿瘤作用的新型、T细胞非依赖性机制。此外，他们将确定抗CD 40 mAb活化的细胞如何用于进一步增强肿瘤疫苗和mAb-IL 2融合蛋白的抗肿瘤作用。 这些结果可以直接应用到临床试验的设计中，可能将CD 40连接与不同形式的免疫治疗相结合。

Stimulation of antigen-presenting cells through their CD40 receptors can induce antitumor T cell responses in some murine tumor models. We have recently shown that an agonistic anti-CD40 mAb can also induce antitumor effects via activation of natural killer (NK) cells, even in the absence of T cells. Our preliminary results suggest that macrophages activated via CD40 ligation may also kill tumor cells in vivo. We also hypothesize that the T cells or NK cells activated by CD40 ligation will cause augmented antitumor destruction when combined with immunotherapeutic reagents designed to activate antitumor T cells (tumor vaccines) or NK cells (immunocytokine fusion proteins), respectively. The purpose of this project is to determine the mechanisms inducing T cell dependent or T cell independent antitumor effects in response to anti-CD40 mAb treatment, identify the specific cells and cytokines involved in these responses, and evaluate the adjuvant antitumor efficacy of anti- CD40 mAb when combined with other forms of immunotherapy. Specifically, we will accomplish this through the following 3 aims: 1. Determine the mechanisms accounting for preferential activation of T cells or NK cells in response to anti-CD40 mAb. 2. Evaluate NK cell and macrophage-mediated mechanisms of antitumor effects induced by anti-CD40 mAb. 3. Determine the role of anti-CD40 mAb in augmenting effects of immunotherapies against poorly immunogenic tumors. Together, these studies will characterize the novel, T cell-independent mechanisms of the antitumor effects induced by anti-CD40 mAb. Furthermore, they will determine how anti-CD40 mAb-activated cells may be used to further augment the antitumor effects of tumor vaccines and mAb-IL2 fusion proteins. These results may be directly implemented into the design of clinical trials potentially combining CD40 ligation with different forms of immunotherapy.