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Regulation of dendritic cell function and tumor immunity by TIM-3

TIM-3对树突状细胞功能和肿瘤免疫的调节

基本信息

批准号：
10218098
负责人：
Brian Ruffell
金额：
$ 39.35万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218098
关键词：
Antibodies Antigens Antitumor Response Breast Cancer Model Breast Cancer Patient Breast Carcinoma CD8-Positive T-Lymphocytes CXCL9 gene CXCR3 gene Cell Communication Cell physiology Cessation of life Combination immunotherapy Combined Modality Therapy Cytotoxic T-Lymphocytes DNA Dendritic Cells Dendritic cell activation Dendritic cell tumor Diagnosis Digestion Disease Environment Gene Expression Profiling Goals Granzyme IFNAR1 gene Immune Immunoglobulins Immunotherapy In Vitro Interferons Ligands Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Mucins Mus Mutation Myelogenous Nucleic Acids PD-1/PD-L1 PD-L1 blockade Paclitaxel Pathway interactions Patients Peripheral Play Population Process Publishing Refractory Regulation Regulatory Pathway Role Stimulator of Interferon Genes Survival Rate System T cell response T-Lymphocyte Therapeutic Intervention Tissues Toll-like receptors Transgenic Model Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Virus Diseases Woman adaptive immune response anti-PD-1 anti-PD-L1 anti-tumor immune response base chemokine chemotherapy combinatorial cytotoxic design draining lymph node exhaust exhaustion immune checkpoint blockade improved in vivo lymph nodes malignant breast neoplasm molecular subtypes mouse model neoplastic cell novel strategies phase 3 study prevent programmed cell death ligand 1 response sensor standard of care targeted treatment tumor tumor growth tumor microenvironment tumor-immune system interactions type I interferon receptor

项目摘要

PROJECT SUMMARY Regulation of dendritic cell function and tumor immunity by TIM-3 Tumor immunity is predicated upon the de novo activation and expansion of antigen-specific cytotoxic T lymphocytes. However, to impact tumor growth these T cells must also infiltrate into tumors, overcome a suppressive environment, and avoid becoming exhausted in the presence of persistent antigen, barriers that are thought to be major impediments to immunotherapy. Conventional dendritic cells are well established as the central inducers of the adaptive immune response, but emerging evidence suggests they may also play in supporting T cell activity within peripheral tissues, including tumors. In support of this, we have found that TIM- 3 (T-cell immunoglobulin and mucin domain containing-3) is highly expressed by tumor dendritic cells, and that TIM-3 blockade induces expression of the chemokine CXCL9 in vitro and in vivo, thereby promoting T cell cytotoxic effector function in models of mammary carcinoma. Here we propose to identify the dendritic cell activation pathways altered by TIM-3, determine if non-migratory dendritic cells maintain T cell function within tumors, and determine the role of CXCL9 expression by dendritic cells in tumor immunity. These studies will delineate a putative dendritic cell regulatory pathway and improve our understanding of the role of dendritic cells within tumors, both factors that may have important implications for the design of combinatorial immunotherapies.

项目概要 TIM-3对树突状细胞功能和肿瘤免疫的调节肿瘤免疫取决于抗原特异性细胞毒性 T 的从头激活和扩增淋巴细胞。然而，为了影响肿瘤生长，这些 T 细胞还必须渗透到肿瘤中，克服抑制环境，并避免在存在持久性抗原、屏障的情况下变得精疲力尽被认为是免疫治疗的主要障碍。传统的树突状细胞已被确定为适应性免疫反应的核心诱导剂，但新出现的证据表明它们也可能在支持外周组织（包括肿瘤）内的 T 细胞活性。为了支持这一点，我们发现 TIM- 3（包含 T 细胞免疫球蛋白和粘蛋白结构域 3）在肿瘤树突细胞中高度表达，并且 TIM-3 阻断诱导趋化因子 CXCL9 在体外和体内的表达，从而促进 T 细胞乳腺癌模型中的细胞毒性效应器功能。在这里我们建议鉴定树突状细胞 TIM-3 改变的激活途径，确定非迁移树突状细胞是否维持 T 细胞功能肿瘤，并确定树突状细胞表达 CXCL9 在肿瘤免疫中的作用。这些研究将描绘假定的树突状细胞调节途径并提高我们对树突状细胞作用的理解肿瘤内的细胞，这两个因素都可能对组合设计产生重要影响免疫疗法。