Leukocyte-Endothelial Adhesion in Tumor Immunity

基于T细胞的癌症免疫治疗依赖于血液中T细胞获得 以启动肿瘤靶点的破坏。在扩大流通领域的同时 效应性T细胞可以通过过继T细胞转移在治疗上获得，总体上成功 免疫治疗策略一直受到限制。我们的研究确定了贩运分子的稀缺性 T细胞进入肿瘤微环境所需的肿瘤微血管。然而，我们 发现全身热疗可以更好地利用肿瘤微环境 (STT)增加作为肿瘤门户的血管内皮细胞的粘附性 纸巾。这些观察结果使我们假设全身热疗(STT)可以改善 靶向性T淋巴细胞转导过继T细胞治疗的疗效观察 肿瘤生长的原发和转移部位。建议的研究是在下列基础上制订的 小鼠肿瘤模型中淋巴细胞-内皮-白介素6(IL-6)轴的鉴定 介导STT的前黏附活性。STT的一个主要粘连目标是血管守门人， 细胞间黏附分子-1(ICAM-1)，它支持血管壁上T细胞的牢固阻止和 跨内皮细胞迁移。在目标1中，我们计划在之前发现的基础上确定STT是否起作用 通过依赖IL-6的机制来修饰额外的运输分子(黏附受体， 趋化因子)在过继免疫治疗的小鼠B16黑色素瘤模型中招募T细胞。 补充原位成像研究将探讨内源性人IL-6在脑出血中的作用 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。在AIM 2 我们将检验这样的假设，即宿主组织环境的预适应通过瞬间 淋巴滤除增强STT对效应T细胞向小鼠黑色素瘤转移的影响 肿瘤组织。该综合疗法对ICAM-1依赖的CD8进入的联合作用 肿瘤组织中的效应性T细胞将使用抗体阻断策略和黏附缺陷来确定 老鼠。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将是 已评估。目标3将检验这一假设，即局部趋化因子可获得性的增强对 肿瘤血管景观可与STT合作，增强CD8T细胞向肿瘤组织的转运 在收养转移期间。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到ICAM-1依赖的牢固停滞的过程中 肿瘤血管将使用缓释微球系统进行探测，以传递CXCL10。这个 拟议的研究有望为T细胞向肿瘤传递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了概念基础。

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.