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Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors

剖析 Runx3 和 Mll1 在 T 细胞对肿瘤的功能失调反应中的作用

基本信息

批准号：
9904112
负责人：
Adam Joshua Getzler
金额：
$ 3.25万
依托单位：
SCRIPPS FLORIDA
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：
2019-04-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904112
关键词：
Acute Address Antigen-Presenting Cells Antigens Antitumor Response Apical Automobile Driving Binding Binding Sites Breast CD8-Positive T-Lymphocytes Cell physiology Cells Chromatin Chromatin Structure Clinical Complex Cytolysis Cytoplasmic Granules Cytotoxic T-Lymphocytes Deposition Development Epigenetic Process Exocytosis Family member Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Epistasis Genetic Transcription Immune Targeting Immunity In Vitro Lead Ligands Link Lymphocyte Function Lymphocytic Infiltrate Lymphocytic choriomeningitis virus MLL gene Maintenance Mediating Memory Methylation Modeling Monoclonal Antibodies Outcome PD-1 blockade Pathway interactions Pattern Phenotype Play Program Accessibility RNA interference screen RUNX3 gene Regulation Research Residencies Role Signal Transduction Solid Neoplasm Stimulus System T cell differentiation T cell response T-Lymphocyte Tissues Transcript Tumor Antigens Tumor-Infiltrating Lymphocytes Viral Antigens Virus Diseases Work acute infection cancer cell chromatin modification cytotoxic experimental study genetic architecture genome-wide histone methylation immune checkpoint blockade in vivo interest melanoma methylation pattern mouse model next generation sequencing novel overexpression programmed cell death protein 1 programs protein expression receptor receptor expression response transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

Project Summary/Abstract: CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), to directly engage malignant cells and cause their lysis via exocytosis of cytotoxic granules. However, the regulation underlying these responses to tumors is ill- defined and generally unsuccessful compared responses to acute viral infections. In addition, studies have shown that while inhibitory signal blockade can restore some T cell function, it does not lead to global epigenetic reprogramming of dysfunctional cells. Nevertheless, basic studies to clarify the factors and mechanisms that control chromatin structure and transcription in CD8 T cells reacting to tumors and viral infection are likely to identify how this can be achieved. To address these issues, I am interested in defining how transcription factor Runx3 and chromatin regulator Mll1 work separately and together to effect genome wide transcript expression, chromatin accessibility, and inhibitory receptor expression in CTLs infiltrating triple negative breast cancers. I provide evidence that both Runx3 and Mll1 expression levels can manipulate PD-1 expression and that Mll1 expression is linked to Runx3. I hypothesize that by studying how these two genes work independently and in a coordinated fashion I can define a network of gene regulation and chromatin accessibility that programs PD-1 expression, and more broadly, understand more about the genetic architecture of CTLs infiltrating non-lymphoid tissues. To do, I propose two specific aims: Elucidate how Runx3 programs CD8+ T cell differentiation during anti-tumor responses & Understand the role of Mll1 in determining CTL function in tumor microenvironments. Both aims will utilize a model of murine triple negative breast cancer, E0771, tagged with lymphocytic choriomeningitis virus antigen GP33 to allow for antigen specific tumor targeting in proposed experiments. In Aim 1, I will identify the key genetic and epigenetic landscapes through which Runx3 acts and how this relates to PD-1 function. Previous research has shown that Runx3 is necessary to generate non-lymphoid and tumor residency and also programs the expression of inhibitory genes such as PD-1. By studying these features, I can identify what pathways this apical transcription factor works through and how this effects PD-1 expression. In Aim 2, I will be investigating the role Mll1 plays in similar pathways. Mll1 was identified through an in vitro RNAi screen for chromatin regulators that modulated co-inhibitory genes. From this screen Mll1, and genes that make up the MLL1/2 complex, are heavily implicated in inhibiting PD-1 expression. By looking at how Mll1 functions in CTLs within the TME and what changes it promotes both in accessibility and methylation, I can understand how these changes in chromatin directs CTL fates in tumors. Combined with understanding Runx3 and the relationship between the genes, this will provide detailed evidence into the fundamental genetic architecture underlying CTLs accumulation and maintenance within tumors.

项目总结/文摘: