权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10523133
负责人：
ALYCIA GARDNER
金额：
$ 9.33万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2019-09-06 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523133
关键词：
Address Affect Antibodies Antigen Presentation Antigens Antitumor Response Bone Marrow Breast Cancer Patient CD8-Positive T-Lymphocytes CTLA4 gene Cell Communication Cell physiology Cells Chemotactic Factors Combined Modality Therapy 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 response T-Lymphocyte Techniques Therapeutic Treatment Efficacy Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells United States Up-Regulation Woman adaptive immune response anti-PD-L1 anti-tumor immune response base 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

项目摘要

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.

项目总结