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

Mechanisms of REST-mediated immunosuppression in cancer

REST 介导的癌症免疫抑制机制

基本信息

批准号：
10749289
负责人：
Daniel E Michaud
金额：
$ 6.91万
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：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749289
关键词：
Agitation Antigens Biological Assay Breast Cancer Cell CD8-Positive T-Lymphocytes CSF1R gene Cancer Etiology Cell secretion Cells Cellular Immunity Cessation of life Characteristics Coculture Techniques Cytometry Data Flow Cytometry Gene Expression Profile Genes Goals Grant Immune Immune response Immunofluorescence Immunologic Immunologist Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Intrinsic factor KDR gene Knock-out Link Lymphangiogenesis Lymphatic Lymphatic Endothelium Lymphocyte Lymphocyte Activation Lymphocyte Function Lymphocyte Suppression Lymphocytic Infiltrate Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Migration Assay Modeling Mus Myelogenous Neurosecretory Systems Outcome Pathway Analysis Patients Periodicity Phenotype Population Positioning Attribute Prognosis Proliferating RNA RNA analysis Refractory Regulation Research Research Proposals Resistance Rest Role Signal Transduction Solid Neoplasm T-Lymphocyte Technical Expertise Testing The Cancer Genome Atlas Therapeutic Training Transcription Repressor Tumor Promotion Tumor-Infiltrating Lymphocytes Tumor-associated macrophages United States Vascular Endothelial Growth Factors Woman Writing anti-PD-1 biomarker discovery biomarker identification cancer cell career chemokine cytokine cytotoxicity effector T cell functional loss immune cell infiltrate immune checkpoint blockade immunoregulation improved in vivo in vivo Model loss of function malignant breast neoplasm molecular subtypes nano-string novel prognostic of survival programmed cell death ligand 1 recruit response skills synergism targeted treatment transcriptome transcriptome sequencing treatment response treatment strategy tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Project Abstract Tumor-intrinsic factors in cancer cells modulate the immune milieu to enable prolonged survival and growth of tumors. In breast cancer (BC), the 2nd leading cause of cancer-related deaths in women, molecular subtyping of these factors effectively guides targeted therapies, but does not guide immunotherapy approaches as immune infiltrates vary significantly within each subtype. The presence of tumor-infiltrating lymphocytes (TILs) is highly prognostic for survival and therapeutic benefit in BC, but the tumor-intrinsic factors governing their presence are not well defined. Using TCGA RNA analysis, I have identified loss of function in the transcriptional repressor REST as being a key correlate to reduced lymphocyte infiltration into tumors of multiple BC molecular subtypes. Loss of functional REST in BC (~15-20% of tumors) is associated with poorer prognoses, however, the mechanisms by which loss of REST function modulates the tumor immune microenvironment are not known and may provide novel targets for enhancing therapeutic responses. I recently generated a murine Rest knockout BC line (Rest-less) and my in vivo studies confirmed that Rest-less tumors contain significantly less lymphocytes while also revealing a significant increase in pro-tumor macrophages, a cell population our lab has identified as being key modulators of lymphocyte suppression in BC. Furthermore, my in vitro studies identified lymphangiogenic Vegfc and Vegfd among the most differentially upregulated genes in Rest-less BC cells. Tumor lymphangiogenesis is linked to T cell suppression in solid tumors and may provide a reason for Rest-mediated suppression of lymphocytes. Based on my preliminary data, I hypothesize that lymphocyte suppression in Rest- less tumors is orchestrated by the polarization of tumor-associated macrophages (TAMs) and lymphatic endothelium to a suppressive phenotype. I propose two specific aims to test my hypothesis. In Aim 1, I will determine the role of tumor intrinsic Rest on TAM-mediated lymphocyte suppression using co-culture assays of TAMs from Rest-less tumors together with lymphocytes in vitro and macrophage depletion through anti-CSF-1R treatment in an antigen-specific (GFP; JEDI) Rest-less model in vivo. In Aim 2, I will evaluate how Vegfr3, the receptor for Vegfc and Vegfd, regulates the REST-less tumor microenvironment and responsiveness to immunotherapy. To accomplish this task, I will test anti-Vegfr3 blockade on Rest-less tumors with or without anti- PD1 and comprehensively analyze tumor growth, lymphatic depletion, and immune responses using RNAseq, spectral cytometry, and cyclic immunofluorescence. Our proposed research will provide an understanding of a previously uncharacterized facet of REST-mediated immune suppression in BC and will use novel murine orthotopic models to test strategies that block immune suppressive mechanisms. Ultimately, I anticipate my findings will reveal targetable mechanism(s) to inhibit Rest-mediated immunosuppression in BC and provide a considerable impact on the treatment of REST-less tumors overall.

项目摘要