Leukocyte-Endothelial Adhesion in Tumor Immunity

肿瘤免疫中的白细胞-内皮粘附

基本信息

批准号：
8387717
负责人：
Sharon S Evans
金额：
$ 30.03万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-13 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387717
关键词：
Address Adhesions Adhesives Adoptive Immunotherapy Adoptive Transfer Antibodies Apoptosis Area Blocking Antibodies Blood Blood Vessels CD8B1 gene CXCL10 gene CXCR3 gene Cell Adhesion Molecules Chemotactic Factors Combined Modality Therapy Cutaneous Melanoma Cytolysis Development Endothelial Cells Environment Extravasation Fever Frequencies Funding Gatekeeping Genetic Goals Growth Hour Human Image Immune Immune response Immunotherapy In Situ Intercellular adhesion molecule 1 Interleukin-6 Investigation Laboratories Lead Leukocytes Link Lymphocyte Malignant - descriptor Mediating Microspheres Modeling Mus Ovalbumin Patients Pre-Clinical Model Prior Therapy Property Reaction Recruitment Activity Regimen Role SCID Mice Site Specimen Staging System T cell therapy T-Lymphocyte Testing Tissues Translating Tumor Immunity Tumor Tissue Vascular Endothelial Cell Work Xenograft Model adhesion receptor arm base cancer immunotherapy cancer therapy chemokine chemokine receptor clinical practice clinically relevant combinatorial conditioning density design human disease improved insight intravital microscopy melanoma migration neoplastic cell novel novel strategies novel therapeutics pre-clinical preconditioning receptor response success targeted delivery thermal stress trafficking tumor tumor growth tumor microenvironment

项目摘要

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.

基于 T 细胞的癌症免疫疗法取决于血源性 T 细胞获取恶性组织以启动肿瘤靶点破坏。在扩大流通池的同时效应T细胞可以通过过继性T细胞转移来实现治疗，总体成功免疫治疗策略受到限制。我们的研究已经确定了贩运分子的缺乏 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有利地利用肿瘤微环境 (STT) 增加血管内皮细胞的粘附特性，血管内皮细胞是肿瘤的门户组织。这些观察结果使我们推测全身热疗 (STT) 可以改善过继性 T 细胞疗法通过靶向递送溶细胞性 T 淋巴细胞至肿瘤生长的原发部位和转移部位。拟议的研究是在以下基础上制定的：在小鼠肿瘤模型中鉴定出一种新型淋巴细胞-内皮细胞-白细胞介素-6 (IL-6) 轴介导 STT 的促粘附活动。 STT的一个主要粘附目标是血管看门人，细胞间粘附分子-1 (ICAM-1)，它支持 T 细胞在血管壁上的牢固停留和跨内皮迁移。在目标 1 中，我们计划基于之前的发现来确定 STT 是否有效通过 IL-6 依赖性机制来修饰额外的运输分子（粘附受体、趋化因子）在过继性免疫疗法的小鼠 B16 黑色素瘤模型中招募 T 细胞。补充原位成像研究将调查内源性人 IL-6 在在人类黑色素瘤的临床前异种移植模型中动员过继转移的 T 细胞。目标 2 我们将检验这样的假设：通过瞬态预处理宿主组织环境淋巴细胞清除放大了 STT 对效应 T 细胞向小鼠黑色素瘤运输的影响肿瘤组织。这种多模式疗法对 ICAM-1 依赖性 CD8 进入的组合效应肿瘤组织中的效应 T 细胞将使用抗体阻断策略和粘附缺陷来定义老鼠。早期T细胞进入肿瘤组织与肿瘤细胞凋亡之间的因果关系是评价。目标 3 将检验以下假设：增强局部趋化因子的可用性肿瘤血管景观可以与 STT 合作增强 CD8 T 细胞向肿瘤组织的运输在收养转移期间。对趋化因子/趋化因子受体对 CXCL10/CXCR3 的要求，介导 T 细胞从最初的滚动相互作用到 ICAM-1 依赖性牢固停滞的转变将使用用于传递 CXCL10 的缓释微球系统来探测肿瘤血管。这拟议的研究有望为 T 细胞递送至肿瘤的机制提供新的见解微环境，并为癌症免疫治疗的新治疗策略提供概念基础。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impact of fever-range thermal stress on lymphocyte-endothelial adhesion and lymphocyte trafficking.

发烧范围的热应激对淋巴细胞-内皮粘附和淋巴细胞运输的影响。

DOI：
发表时间：
2005
期刊：
影响因子：
2.8
作者：
Appenheimer, Michelle M;Chen, Qing;Girard, Rachael A;Wang, Wan;Evans, Sharon S
通讯作者：
Evans, Sharon S

Thermal regulation of lymphocyte trafficking: hot spots of the immune response.

淋巴细胞运输的热调节：免疫反应的热点。

DOI：
发表时间：
2005-12
期刊：
影响因子：
0
作者：
Chen, Qing;Evans, Sharon S
通讯作者：
Evans, Sharon S

Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance.

发烧范围热应激对淋巴细胞-内皮-IL-6转信号轴的调节：免疫监视的热点。

DOI：
10.1016/j.cyto.2007.07.184
发表时间：
2007-07-01
期刊：
Cytokine
影响因子：
3.8
作者：
Trupti D. Vardam;Lei Zhou;M. Appenheimer;Qing Chen;Wan‐Chao Wang;H. Baumann;S. Evans
通讯作者：
S. Evans

Tumor microvasculature as a barrier to antitumor immunity.

肿瘤微血管系统作为抗肿瘤免疫的屏障。

DOI：
发表时间：
2003-11
期刊：
影响因子：
0
作者：
Chen, Qing;Wang, Wan;Evans, Sharon S
通讯作者：
Evans, Sharon S

Coordinate regulation of lymphocyte-endothelial interactions by pregnancy-associated hormones.

妊娠相关激素对淋巴细胞-内皮相互作用的协调调节。

DOI：
发表时间：
2003-10-15
期刊：
影响因子：
0
作者：
Chantakru, Sirirak;Wang, Wan;van den Heuvel, Marianne;Bashar, Siamak;Simpson, Amanda;Chen, Qing;Croy, B Anne;Evans, Sharon S
通讯作者：
Evans, Sharon S