Targeting the Epigenome to Improve Responses to Immunotherapy

靶向表观基因组以改善免疫疗法的反应

• 批准号: 10548236
• 负责人: ALYCIA GARDNER
• 金额: $ 9.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548236
• 关键词: Address; Affect; Antibodies; Antigen Presentation; Antitumor Response; Bone Marrow; Breast Cancer Patient; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell Communication; Cells; Chemotactic Factors; Combined Modality Therapy; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Diagnosis; Disease; Future; Gene Expression Profiling; Human; Immune; Immune response; Immunity; Immunoglobulins; Immunotherapeutic agent; Immunotherapy; Infection; Intervention; Location; Mammary Neoplasms; Masks; Measures; Mediating; Modality; Modeling; Mucins; Mus; Mutation; Paclitaxel; Pathway interactions; Patients; Phase; Population; Production; Publishing; Regulation; Research; Role; Scanning; Site; Survival Rate; T cell differentiation; T cell infiltration; T cell response; T-Lymphocyte; Techniques; Therapeutic; Treatment Efficacy; Tumor Antigens; Tumor Immunity; United States; Up-Regulation; Woman; adaptive immune response; anti-PD-L1; anti-tumor immune response; cancer diagnosis; chemokine; chemotherapy; combinatorial; cytokine; design; draining lymph node; effective therapy; epigenome; experimental study; immune checkpoint blockade; improved; in vivo imaging; lymph nodes; malignant breast neoplasm; migration; molecular subtypes; mouse model; phase 3 study; programmed cell death ligand 1; programmed cell death protein 1; response; secondary lymphoid organ; standard of care; treatment response; tumor; tumor microenvironment

Project Summary Conventional dendritic cells (cDCs) are central regulators of the adaptive immune response, and have been shown to be required for the induction of T cell-mediated anti-tumor immunity. In particular, a subset of cDCs (cDC1) is responsible for transporting tumor antigens to the lymph node and cross presenting antigen in order to activate cytotoxic T lymphocytes, thereby inducing an anti-tumor response. We have recently observed TIM- 3 (T-cell immunoglobulin and mucin domain containing-3) expression on cDCs in human and murine mammary tumors, and found that TIM-3 blockade improved response to standard-of-care paclitaxel chemotherapy in models of triple-negative and luminal B disease. This occurred through increased chemokine expression by cDCs, without a corresponding in T cell infiltration, leading me to hypothesize that the spatial localization of cDCs and T cells within tumors is a critical determinant of successfully immunotherapy. In the F99 portion of this application I will therefore seek to determine if TIM-3 blockade alters the spatial organization of T cells, and if this is responsible for therapeutic efficacy. In the K00 phase of this proposal I will expand these studies to evaluate whether cDC/T cell clustering is a prerequisite for response to immune checkpoint blockade and other therapeutic modalities.

项目摘要 常规的树突状细胞（cDC）是适应性免疫应答的中心调节因子，并且已经被广泛应用。 显示为诱导T细胞介导的抗肿瘤免疫所需。特别是，cDC的一个子集 cDC 1负责将肿瘤抗原转运至淋巴结并交叉呈递抗原， 以激活细胞毒性T淋巴细胞，从而诱导抗肿瘤应答。我们最近观察到， 3（含T细胞免疫球蛋白和粘蛋白结构域-3）在人和鼠乳腺癌中cDC上的表达 并发现TIM-3阻断剂改善了对标准护理紫杉醇化疗的反应， 三阴性和管腔型B疾病的模型。这是通过增加趋化因子表达而发生的， cDCs，没有相应的T细胞浸润，这使我假设， 肿瘤内的cDC和T细胞是成功免疫治疗的关键决定因素。在F99部分， 因此，本申请将寻求确定TIM-3阻断是否改变T细胞的空间组织， 如果这是治疗效果的原因。在本提案的K 00阶段，我将扩大这些研究， 评估cDC/T细胞聚集是否是对免疫检查点阻断和其他免疫应答的先决条件。 治疗方式