USING NOVEL TNF RECEPTORS TO ENHANCE IMMUNOTHERAPY

在这项提案中，我们将重点关注CD 4肿瘤免疫，目标是产生对肿瘤抗原特异性的长寿命CD 4+“记忆”T细胞，这些T细胞反过来应与CD 8 T细胞协同作用，以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CD 4 + T细胞。 OX-40受体是膜结合和可溶性细胞因子受体家族的淋巴细胞特异性成员，该家族已被称为肿瘤坏死因子受体（TNF-R）超家族。 除TNF受体外，该家族还包含CD 30抗原、CD 40、FAS（CD 95）、DR 3和4-1BB，所有这些都主要在造血谱系细胞上表达。 OX-40受体是主要在活化的CD 4 + T细胞上发现的膜相关糖蛋白，并且在正常静息的外周血淋巴细胞上不表达。 最近，我们和其他人已经表明，OX-40受体可以提供一个有效的共刺激信号，以驱动T细胞增殖，这种刺激似乎是更明显的效应T细胞阶段，而不是幼稚T细胞阶段。 我们还表明，从表达OX-40受体的实验性自身免疫性脑脊髓炎（EAE）的炎性病变中分离的T细胞高度富集了对自身抗原应答的T细胞。 最近在癌症患者的炎症部位（肿瘤和肿瘤引流淋巴结）的CD 4 + T细胞上发现了OX-40受体。 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，并在自体肿瘤疫苗接种的宿主中产生增强的肿瘤特异性应答。 此外，我们将尝试通过结合4-1BB受体来进一步增强T细胞特异性肿瘤免疫，4-1BB受体已显示在肿瘤环境中增强CD 8 + T细胞功能。 我们还将尝试通过阻断活化T细胞上表达的DR 3“死亡结构域”受体来阻断肿瘤抗原特异性T细胞中活化诱导的细胞死亡。 在肿瘤环境中操纵3种TNF受体家族成员的组合应有助于获得对CD 4+和CD 8 + 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.