Leukocyte-Endothelial Adhesion in Tumor Immunity

肿瘤免疫中的白细胞-内皮粘附

• 批准号: 8196824
• 负责人: Sharon S Evans
• 金额: $ 31.5万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-13 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196824
• 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

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细胞的癌症免疫治疗依赖于血源性T细胞进入肿瘤的能力