T-Cell Independent Antitumor Mechanisms of CD40 Ligation

在某些小鼠肿瘤模型中，通过CD40受体刺激抗原提呈细胞可以诱导抗肿瘤T细胞反应。我们最近发现，激动型抗CD40单抗也可以通过激活自然杀伤细胞(NK细胞)来诱导抗肿瘤作用，即使在没有T细胞的情况下也是如此。我们的初步结果表明，通过CD40结扎激活的巨噬细胞也可以在体内杀死肿瘤细胞。我们还假设，CD40结扎激活的T细胞或NK细胞分别与旨在激活抗肿瘤T细胞(肿瘤疫苗)或NK细胞(免疫细胞因子融合蛋白)的免疫治疗试剂结合时，将导致更大的抗肿瘤破坏。本课题的目的是确定抗CD40单抗诱导T细胞依赖或非T细胞非依赖性抗肿瘤效应的机制，鉴定参与这些反应的特异性细胞和细胞因子，并评价抗CD40单抗与其他形式的免疫治疗联合应用的佐剂抗肿瘤效果。具体地说，我们将通过以下三个目标来实现这一点：1.确定抗CD40单抗优先激活T细胞或NK细胞的机制。2.探讨抗CD40单抗诱导NK细胞和巨噬细胞介导的抗肿瘤作用机制。3.确定抗CD40单抗在增强免疫原性低的肿瘤免疫治疗效果中的作用。总之，这些研究将描述抗CD40单抗诱导的抗肿瘤作用的新的、T细胞无关的机制。此外，他们将确定如何使用抗CD40单抗激活的细胞来进一步增强肿瘤疫苗和单抗-IL2融合蛋白的抗肿瘤效果。这些结果可以直接应用到临床试验的设计中，有可能将CD40结扎与不同形式的免疫治疗结合起来。

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.