Leukocyte-Endothelial Adhesion in Tumor Immunity

描述（由申请人提供）： 基于T细胞的癌症免疫疗法依赖于血液传播的T细胞进入恶性组织的能力，以启动肿瘤靶向破坏。虽然通过过继性T细胞转移可以在治疗上实现循环效应T细胞库的扩增，但免疫治疗策略的总体成功受到限制。我们的研究已经确定了肿瘤微血管上T细胞进入肿瘤微环境所需的运输分子的缺乏。然而，我们已经发现，肿瘤微环境可以有利地利用全身热疗法（STT），以增加血管内皮细胞的粘附特性，作为肿瘤组织的门户。这些观察使我们假设全身热疗法（STT）可以通过靶向将溶细胞性T淋巴细胞递送至肿瘤生长的原发性和转移性位点来提高过继性T细胞疗法的功效。拟定的研究制定的基础上，一个新的淋巴细胞-内皮细胞-白细胞介素-6（IL-6）轴在小鼠肿瘤模型中介导的促粘附活性的STT的鉴定。STT的主要粘附靶点是血管守门人细胞间粘附分子-1（ICAM-1），其支持T细胞在血管壁上的牢固阻滞和跨内皮迁移。在目标1中，我们计划建立在我们以前的研究结果，以确定STT是否通过IL-6依赖性机制来修饰在过继免疫治疗的小鼠B16黑色素瘤模型中招募T细胞的其他运输分子（粘附受体，趋化因子）。补充原位成像研究将调查内源性人IL-6在人黑色素瘤临床前异种移植模型中动员过继转移的T细胞的贡献。在目标2中，我们将检验这样的假设，即通过瞬时淋巴细胞耗竭对宿主组织环境进行预处理，放大了STT对效应T细胞向小鼠黑色素瘤肿瘤组织运输的影响。将使用抗体阻断策略和粘附缺陷小鼠来定义这种多模式疗法对肿瘤组织中CD 8效应T细胞的ICAM-1依赖性进入的组合效应。将评价早期T细胞进入肿瘤组织和肿瘤细胞凋亡之间的因果关系。目的3将检验肿瘤血管景观上局部趋化因子可用性的增强可以与STT协作以增强过继转移期间CD 8 T细胞向肿瘤组织的运输的假设。趋化因子/趋化因子受体对CXCL 10/CXCR 3在介导T细胞从初始滚动相互作用转变为肿瘤血管中的ICAM-1依赖性牢固停滞中的需求将使用用于递送CXCL 10的缓释微球系统来探测。这些研究有望为T细胞向肿瘤微环境递送的机制提供新的见解，并为癌症免疫治疗的新治疗策略提供概念基础。

DESCRIPTION (provided by applicant): T cell-based cancer immunotherapy depends on the ability of blood-borne T cells to gain access to malignant tissues in order to initiate tumor-target destruction. While expansion of the pool of circulating effector T cells can be achieved therapeutically by adoptive T cell transfer, the overall success of immunotherapy strategies has been limited. Our studies have defined a paucity of trafficking molecules on tumor microvessels that are required for T cell entry into the tumor microenvironment. However, we have discovered that the tumor microenvironment can be exploited favorably by systemic thermal therapy (STT) to increase the adhesive properties of vascular endothelial cells that serve as gateways to tumor tissues. These observations lead us to hypothesize that systemic thermal therapy (STT) can improve the efficacy of adoptive T cell therapy by targeting the delivery of cytolytic T lymphocytes to primary and metastatic sites of tumor growth. The proposed studies are formulated on the basis of the identification of a novel lymphocyte-endothelial-interleukin-6 (IL-6) axis in murine tumor models that mediates the proadhesive activities of STT. A major adhesive target of STT is the vascular gatekeeper, intercellular adhesion molecule-1 (ICAM-1), which supports both firm arrest of T cells on vessel walls and transendothelial migration. In Aim 1 we plan to build on our previous findings to determine if STT acts through an IL-6-dependent mechanism to modify additional trafficking molecules (adhesion receptors, chemokines) that recruit T cells in a murine B16 melanoma model of adoptive immunotherapy. Complementary in situ imaging studies will investigate the contribution of endogenous human IL-6 in mobilizing adoptively transferred T cells in a preclinical xenograft model of human melanoma. In Aim 2 We will test the hypothesis that preconditioning of the host tissue environment by transient lymphodepletion amplifies the effects of STT on the trafficking of effector T cells to murine melanoma tumor tissues. The combinatorial effects of this multimodality therapy on ICAM-1-dependent entry of CD8 effector T cells in tumor tissues will be defined using antibody-blocking strategies and adhesion-deficient mice. A causal relationship between early T cell entry into tumor tissues and tumor cell apoptosis will be evaluated. Aim 3 will test the hypothesis that enhancement of the local chemokine availability on the tumor vascular landscape can collaborate with STT to enhance CD8 T cell trafficking to tumor tissues during adoptive transfer. The requirement for the chemokine/chemokine receptor pair, CXCL10/CXCR3, in mediating the transition of T cells from initial rolling interactions to ICAM-1-dependent firm arrest in tumor vessels will be probed using a sustained-release microsphere system for delivery of CXCL10. The proposed studies are expected to provide new insights into mechanisms of T cell delivery to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy.