CHARACTERISTICS OF T CELLS MEDIATING TUMOR IMMUNOTHERAPY

描述：（申请人的摘要）肿瘤反应性的过继转移 T淋巴细胞介导已确定的恶性肿瘤的消退。 在动物 模型中，肿瘤引流淋巴结（LN）是致敏T的丰富来源 可以离体激活以获得效应子功能的细胞。 在这 应用肿瘤致敏T淋巴细胞在LN中的产生， 该群体的富集和效应细胞功能的分析将 追究 过继免疫治疗的明确定义的小鼠肿瘤模型 将被用来检验抗原呈递细胞 将肿瘤抗原转移到引流LN。 几种佐剂，包括GM-CSF 将瘤旁注射以研究LN T细胞的增强 致敏 在引流淋巴结中，抗原致敏的T细胞显示出改变的 几种膜标志物的水平，其中包括CD 62 L（L-选择素），这将 用于从无关的T细胞中富集肿瘤致敏细胞。 的 与肿瘤细胞接触时细胞因子的产生和治疗 将在分离的T细胞亚群中分析功效。 调解 肿瘤消退T细胞必须接触肿瘤并转移细胞浸润 肿瘤，甚至在免疫特权部位，如中枢神经系统。 转移的T细胞归巢到肿瘤和效应机制将是 在携带颅内肿瘤的小鼠中分析。 细胞粘附分子 将定义介导T细胞粘附于肿瘤血管系统的 通过它们在从肿瘤分离的T细胞上的原位表达， 通过阻断mAb干扰肿瘤浸润。 T细胞介导的肿瘤 回归是高度具体的，选择性贩运的贡献 或肿瘤反应性细胞对该特异性的保留。 虽然离体活化的T细胞在标准51 Cr中不溶细胞， 在释放测定中，它们在与肿瘤接触时确实产生细胞因子。 的 体内细胞因子的产生，以及辅助细胞参与 将研究肿瘤消退的介导。

DESCRIPTION: (Applicant's Abstract) The adoptive transfer of tumor-reactive T lymphocytes mediates regression of established malignancies. In animal models, tumor-draining lymph nodes (LN) are a rich source of sensitized T cells that can be activated ex vivo to acquire effector function. In this application the generation of tumor-sensitized T lymphocytes in LN, enrichment of this population, and analysis of effector cell function will be investigated. Well defined murine tumor models of adoptive immunotherapy will be utilized to test the hypothesis that antigen presenting cells transfer tumor antigens to draining LN. Several adjuvants including GM-CSF will be injected paratumorally to study augmentation of LN T cell sensitization. In the draining LN, antigen primed T cells display altered levels of several membrane markers, among them CD62L (L-selectin), that will be used to enrich tumor-sensitized cells from irrelevant T cells. The production of cytokines upon contact with tumor cells and therapeutic efficacy will be analyzed in the segregated T cell subsets. To mediate tumor regression T cells must contact tumor and transferred cells infiltrate tumors even in immune privileged sites such as the central nervous system. The homing of transferred T cells to tumor and effector mechanisms will be analyzed in mice bearing intracranial tumors. The cell adhesion molecules that mediate adherence of T cells to the tumor vasculature will be defined by their expression in situ, on T cells isolated from tumors, and by interference with tumor infiltration by blocking mAb. T cell mediated tumor regression is highly specific and the contribution of selective trafficking or retention of tumor-reactive cells to this specificity will be determined. Although ex vivo activated T cells are not cytolytic in the standard 51Cr release assay, they do produce cytokines upon contact with tumor. The production of cytokines in vivo, and the participation of accessory cells in mediation of tumor regression will be investigated.