Leukocyte-Endothelial Adhesion in Tumor Immunity

描述（由申请人提供）：成功的免疫疗法最终取决于免疫效应细胞迁移至肿瘤组织的能力。这一过程在肿瘤微环境中受到粘附分子和趋化因子的分子阵列的有限表达的影响，所述粘附分子和趋化因子充当控制淋巴细胞外渗穿过血管内皮屏障的守门人。该提议解决了中心假设，即发热范围的热刺激与局部递送趋化因子相结合，可以促进免疫效应细胞向肿瘤组织的有效募集。这些研究的基础上制定的新信息，发热范围的热应力和趋化因子的行为，通过合作机制，以促进淋巴细胞粘附到血管内皮细胞的目标。提出了三种独立但互补的方法来解决我们的假设：（1）提出了研究发热范围全身热疗治疗荷瘤小鼠（RIP-Tag 5转基因胰腺肿瘤和结肠26同源肿瘤）与趋化因子递送方法的联合作用的策略，以确定是否可以启动改善的淋巴细胞募集。肿瘤微血管的局部趋化因子呈递将通过局部递送淋巴趋化因子蛋白（即，SLC，EFL）或通过IFN-γ依赖性细胞因子级联激活趋化因子生物合成。(2)基于我们的研究暗示IL-6作为淋巴细胞中热粘附的中心介体，研究设计为使用中和抗体和精氨酸缺陷小鼠研究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/微血管中的促粘附活性。(3)淋巴细胞-内皮细胞粘附反应的分子机制，以发热范围的热应力将阐明结合生物化学，分子和药理学的方法。这些研究集中在IL-6依赖的ERK 1/2 MAPK和STAT 3信号转导通路的贡献在体外和体内。拟议的研究预计将提供一个框架，为未来的发热范围的热应激和趋化因子联合输送作为辅助治疗癌症的疗效评价。

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.