Leukocyte-Endothelial Adhesion in Tumor Immunity

描述(由申请人提供)： 基于T细胞的癌症免疫治疗依赖于血液携带的T细胞进入恶性组织的能力，以启动肿瘤靶点的破坏。虽然通过过继T细胞转移可以在治疗上实现循环效应T细胞池的扩大，但免疫治疗策略的总体成功一直是有限的。我们的研究确定了肿瘤微血管上缺乏运输分子，这是T细胞进入肿瘤微环境所必需的。然而，我们发现，全身热疗(STT)可以很好地利用肿瘤微环境，增加作为肿瘤组织门户的血管内皮细胞的粘附性。这些观察结果使我们假设，系统热疗(STT)可以通过靶向将溶细胞T淋巴细胞输送到肿瘤生长的原发和转移部位来提高过继T细胞治疗的疗效。所提出的研究是基于在小鼠肿瘤模型中发现了一个新的淋巴细胞-内皮-白介素6(IL-6)轴，该轴介导了STT的前黏附活性。STT的一个主要黏附靶点是血管守门人细胞间黏附分子-1(ICAM-1)，它支持T细胞在血管壁上的牢固阻止和跨内皮细胞的迁移。在目标1中，我们计划以我们以前的发现为基础，确定STT是否通过依赖IL-6的机制来修改在过继免疫治疗的小鼠B16黑色素瘤模型中招募T细胞的额外运输分子(黏附受体、趋化因子)。补充的原位成像研究将调查内源性人IL-6在动员临床前人类黑色素瘤异种移植模型中过继转移的T细胞方面的作用。在目标2中，我们将检验这样一种假设，即通过瞬时淋巴耗竭对宿主组织环境进行预适应可以放大STT对效应T细胞向小鼠黑色素瘤组织运输的影响。这种多模式疗法对依赖ICAM-1的CD8效应T细胞进入肿瘤组织的联合作用将通过抗体阻断策略和黏附缺陷小鼠来确定。将评估早期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将验证这样的假设，即在过继转移过程中，增强肿瘤血管表面局部趋化因子的可获得性可以与STT协同增强CD8T细胞向肿瘤组织的运输。趋化因子/趋化因子受体对CXCL10/CXCR3在介导T细胞从最初的滚动相互作用转变为肿瘤血管中依赖ICAM-1的牢固停滞过程中的需求将通过用于传递CXCL10的缓释微球系统来探讨。这些研究有望为T细胞转运到肿瘤微环境的机制提供新的见解，并为肿瘤免疫治疗的新治疗策略提供概念上的基础。 公共卫生相关性： 尽管在癌症免疫治疗策略的开发方面取得了相当大的进展，但这些治疗方法的总体影响微乎其微，晚期患者的治疗选择仍然有限。这项建议是基于我们的研究结果提出的，即全身热疗是一种新的方法，目的是将肿瘤特异性细胞溶解T淋巴细胞输送到肿瘤微环境，从而克服基于T细胞的免疫治疗的重大障碍。这些研究有望为靶向向肿瘤微环境输送效应性T细胞的动力学机制提供必要的见解，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. PUBLIC HEALTH RELEVANCE: Despite considerable progress in the development of immunotherapy strategies in cancer, these therapies have had minimal overall impact and treatment options continue to be limited for advanced-stage patients. This proposal is formulated based on our findings that systemic thermal therapy is a novel approach to target the delivery of tumor-specific cytolytic T lymphocytes to the tumor microenvironment, thereby overcoming a significant barrier to T cell-based immunotherapy. The proposed studies are expected to provide needed insights into the dynamic mechanisms that underlie targeted delivery of effector T cells to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy.