USING NOVEL TNF RECEPTORS TO ENHANCE IMMUNOTHERAPY

在这项建议中，我们将重点关注CD_4肿瘤免疫，目标是产生针对肿瘤抗原的长寿命CD_4+“记忆”T细胞(S)，它应该反过来与CD_8T细胞协同作用，产生持久的肿瘤免疫。我们将尝试通过靶向OX-40受体在体内激活肿瘤特异性的CD4+T细胞。OX-40受体是膜结合和可溶性细胞因子受体家族中一个淋巴细胞特异性的成员，该家族被称为肿瘤坏死因子受体(TNF-R)超家族。除肿瘤坏死因子受体外，该家族还包括CD30抗原、CD40、Fas(CD95)、DR3和4-1BB，所有这些都主要表达在造血系细胞上。OX-40受体是一种膜相关糖蛋白，主要存在于活化的CD4+T细胞上，在正常静息状态的外周血淋巴细胞上不表达。最近，我们和其他人已经证明，OX-40受体可以提供强大的共刺激信号来驱动T细胞的增殖，并且这种刺激似乎在效应性T细胞阶段比初始T细胞阶段更明显。我们还发现，从实验性自身免疫性脑脊髓炎(EAE)炎性病变中分离出的表达OX-40受体的T细胞，对于自身抗原应答的T细胞具有高度的浓缩作用。OX-40受体最近在癌症患者炎症部位(肿瘤和肿瘤引流淋巴结)的CD4+T细胞上被发现。因此，我们应该能够在体内通过OX-40受体靶向和激活/共刺激抗原特异性T细胞，并在接种自体肿瘤的宿主中产生增强的肿瘤特异性反应。此外，我们将尝试通过结合4-1BB受体进一步增强T细胞特异性肿瘤免疫，该受体已被证明在肿瘤环境中增强CD8+T细胞功能。我们还将试图通过阻断表达在激活的T细胞上的DR3“死亡结构域”受体来阻止肿瘤抗原特异性T细胞的激活诱导的细胞死亡。在肿瘤环境中操纵3个肿瘤坏死因子受体家族成员的组合，应该有助于获得对CD4+和CD8+T细胞的长期肿瘤免疫。

In this proposal, we will focus on CD4 tumor immunity with the goal of generating long-lived CD4+ "memory" T cells specific for tumor antigen(s) that should in turn synergize with CD8 T cells to create long-lasting tumor immunity. We will attempt to activate tumor-specific CD4+ T cells in vivo by targeting the OX- 40 receptor. The OX-40 receptor is a lymphocyte-specific member of a growing family of receptors for membrane-bound and soluble cytokines that has been termed the tumor necrosis factor receptor (TNF-R) superfamily. In addition to the TNF-receptors, this family also contains the CD30 antigen, CD40, FAS (CD95), DR3, and 4-1BB, all of which are expressed predominantly on cells of haematopoietic lineage. The OX-40 receptor is a membrane-associated glycoprotein found primarily on activated CD4+ T cells and is not expressed on normal resting peripheral blood lymphocytes. Recently, we and others have shown that the OX-40 receptor can provide a potent costimulatory signal to drive T cell proliferation, and that this stimulus appears to be more pronounced at the effector T cell stage rather than the naive T cell stage. We have also shown that T cells isolated from inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), which expressed the OX-40 receptor, were highly enriched for the T cells responding to autoantigen. The OX-40 receptor has recently been found on CD4+ T cells at the site of inflammation in cancer patients (tumors and tumor draining lymph nodes). Therefore, we should be able to target and activate/costimulate antigen-specific T cells via the OX-40 receptor in vivo and create an enhanced tumor-specific response in hosts vaccinated with autologous tumor. In addition we will try to further enhance T cell specific tumor immunity by engaging the 4-1BB receptor which has shown to enhance CD8+ T cell function in a tumor setting. We will also attempt to block activation induced cell death in tumor-antigen specific T cells by blocking the DR3 "death domain" receptor expressed on activated T cells. Manipulating the combination of the 3 TNF-receptor family members in a tumor setting should help attain long-lived tumor immunity for both CD4+ and CD8+ T cells.