Leukocyte-Endothelial Adhesion in Tumor Immunity

肿瘤免疫中的白细胞-内皮粘附

• 批准号: 6749014
• 负责人: Sharon S Evans
• 金额: $ 32.72万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-13 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749014
• 关键词: antibody; biological signal transduction; cell adhesion; cell migration; chemokine; cytokine receptors; cytotoxic T lymphocyte; enzyme activity; enzyme inhibitors; genetically modified animals; hyperthermia; interferon gamma; interleukin 1; interleukin 6; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; neoplasm /cancer immunotherapy; pancreas neoplasms; protein localization; selectins; tumor necrosis factor alpha; vascular cell adhesion molecule

DESCRIPTION (provided by applicant): Successful immunotherapy ultimately depends on the ability of immune effector cells to migrate to tumor tissues. This process is compromised in tumor microenvironments by limited expression of the molecular array of adhesion molecules and chemokines that function as gatekeepers controlling lymphocyte extravasation across the vascular endothelial barrier. This proposal addresses the central hypothesis that fever-range thermal stimulation, in combination with local delivery of chemokines, can promote efficient recruitment of immune effector cells to tumor tissues. These studies are formulated on the basis of new information that fever-range thermal stress and chemokines act through cooperative mechanisms to promote lymphocyte adhesion to vascular endothelial cell targets. Three independent but complementary approaches are proposed to address our hypothesis: (1) Strategies are proposed to examine the combined effects of fever-range whole body hyperthermia treatment of tumor bearing mice (pancreatic tumors of RIP-Tag5 transgenics and colon 26 syngeneic tumors) with chemokine delivery approaches in order to determine if improved lymphocyte recruitment can be initiated. Regional chemokine presentation by tumor microvessels will be induced either by local delivery of lymphotactic chemokine proteins (i.e., SLC, MIG) or activation of chemokine biosynthesis by IFN-gamma-dependent cytokine cascades. (2) Based on our studies implicating IL-6 as a central mediator of thermal adhesion in lymphocytes, studies are designed to investigate the proadhesive activity of IL- 6/soluble IL-6 receptor complexes and other proinflammatory cytokines (TNF-alpha, IL-1beta, and IFN-gamma) in intratumora/microvesse/s using neutralizing antibodies and cytokine-deficient mice. (3) The molecular mechanisms underlying lymphocyte-endothelial adhesion responses to fever-range thermal stress will be elucidated using combined biochemical, molecular, and pharmacologic approaches. These studies focus on the contributions of IL-6-dependent ERK1/2 MAPK and STAT3 signal transduction pathways in vitro and in vivo. The proposed studies are expected to provide a framework for future evaluation of the efficacy of combined fever-range thermal stress and chemokine delivery as adjuvant therapies in the treatment of cancer.

描述（由申请人提供）：成功的免疫治疗最终取决于免疫效应细胞向肿瘤组织迁移的能力。这一过程在肿瘤微环境中由于粘附分子和趋化因子的分子阵列的有限表达而受到损害，这些分子阵列起着控制淋巴细胞穿过血管内皮屏障外渗的看门人的作用。该建议解决了一个中心假设，即发热范围的热刺激，结合局部趋化因子的递送，可以促进免疫效应细胞有效地募集到肿瘤组织。这些研究是基于发热范围的热应激和趋化因子通过合作机制促进淋巴细胞粘附到血管内皮细胞靶点的新信息而制定的。提出了三种独立但互补的方法来解决我们的假设：(1)提出了策略，以检查发热范围全身热疗治疗荷瘤小鼠（ip - tag5转基因胰腺肿瘤和结肠26同基因肿瘤）与趋化因子递送方法的联合效应，以确定是否可以启动改善淋巴细胞募集。肿瘤微血管的局部趋化因子呈递可以通过局部传递淋巴趋化因子蛋白（如SLC、MIG）或ifn - γ依赖性细胞因子级联激活趋化因子生物合成来诱导。(2)基于我们对IL-6作为淋巴细胞热粘附中枢介质的研究，我们设计了研究IL-6 /可溶性IL-6受体复合物和其他促炎细胞因子（tnf - α， IL-1 β和ifn - γ）在瘤内/微血管/s中的促粘附活性，使用中和抗体和细胞因子缺陷小鼠。(3)淋巴细胞-内皮细胞对热应激反应的分子机制将通过生物化学、分子和药理学的方法来阐明。这些研究主要关注il -6依赖性的ERK1/2 MAPK和STAT3信号转导通路在体外和体内的作用。拟议的研究预计将为未来评估联合发热范围热应激和趋化因子递送作为辅助治疗癌症的疗效提供一个框架。