Leukocyte-Endothelial Adhesion in Tumor Immunity

描述(申请人提供)：成功的免疫治疗最终取决于免疫效应细胞迁移到肿瘤组织的能力。在肿瘤微环境中，这一过程受到黏附分子和趋化因子分子阵列的有限表达的影响，这些分子阵列起着控制淋巴细胞通过血管内皮屏障外溢的守门人的作用。这项建议解决了核心假设，即发热范围的热刺激，结合局部递送趋化因子，可以促进免疫效应细胞有效地募集到肿瘤组织。这些研究是基于新的信息制定的，即发热范围内的热应激和趋化因子通过协同机制促进淋巴细胞与血管内皮细胞靶标的黏附。提出了三种独立但互补的方法来解决我们的假设：(1)提出了三种策略来研究发热范围全身热疗对荷瘤小鼠(RIP-Tag5转基因胰腺肿瘤和结肠26同基因肿瘤)的联合影响，以确定是否可以启动改善淋巴细胞募集的方法。局部淋巴趋化因子蛋白(即SLC、MIG)或干扰素-γ依赖的细胞因子级联激活趋化因子生物合成可诱导肿瘤微血管的局部趋化因子递呈。(2)基于IL-6是淋巴细胞热黏附的中枢介质的研究，本研究利用中和抗体和细胞因子缺陷小鼠，研究了IL-6/可溶性IL-6受体复合体和其他促炎细胞因子(肿瘤坏死因子-α、IL-1β和干扰素-γ)在肿瘤/微囊/S中的促黏附活性。(3)采用生化、分子和药理学相结合的方法，阐明热应激下淋巴细胞-内皮细胞黏附反应的分子机制。这些研究主要集中在IL-6依赖的ERK1/2MAPK和STAT3信号转导通路在体内外的作用。预计拟议的研究将为未来评估联合应用热应激和趋化因子作为癌症辅助治疗方法的有效性提供一个框架。

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.