Determining the role of AIRE and AIRE-expressing tumor associated macrophages in tumor growth and immunity

确定 AIRE 和表达 AIRE 的肿瘤相关巨噬细胞在肿瘤生长和免疫中的作用

基本信息

批准号：
10596378
负责人：
Sophia Guldberg
金额：
$ 3.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2023-03-18 至 2026-03-17
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596378
关键词：
ATAC-seq Antibodies Antigens Antitumor Response Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving Biological Assay Biology Bone Marrow CD4 Positive T Lymphocytes California Cancer Etiology Cell surface Cells Cellular biology Chromatin Chromosome Mapping Coculture Techniques Cytometry Data Data Set Development Environment Epigenetic Process Equilibrium Fellowship Flow Cytometry Frequencies Funding Gene Expression Generations Genetic Genetic Transcription Goals Health Hematopoietic Human ITGAM gene Immune Immune response Immunology Immunotherapy In Vitro Institution Investigation Knock-out Laboratories MC38 Macrophage Malignant Neoplasms Mentorship Methods Modeling Mus Mutation Myeloid Cells Pathway interactions Peripheral Phenotype Play Polyglandular Autoimmune Syndrome Type I Population Regulation Regulator Genes Research Research Project Grants Role San Francisco Signal Pathway Solid Neoplasm Stimulant Syndrome System TNFRSF5 gene TNFSF11 gene TNFSF5 gene Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Training Tumor Immunity Tumor-associated macrophages Universities Work anti-CTLA4 anti-PD-1 anti-tumor immune response autoreactive T cell cancer immunotherapy cancer therapy career cell type central tolerance epigenomics gene function gene induction human RNA sequencing immune activation immune checkpoint blockade immunoregulation immunosuppressive macrophages improved in vivo knockout gene melanoma mouse model neoplastic cell novel novel therapeutics patient response peripheral tolerance prevent programs research and development response secondary lymphoid organ single cell analysis single-cell RNA sequencing skills synergism systemic autoimmunity therapy resistant tool transcriptome sequencing tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT AutoImmune Regulator gene (AIRE) prevents autoimmunity by promoting thymic deletion of self-reactive T cells. While most studied in the thymus, AIRE is also expressed in secondary lymphoid organs, where it is thought to contribute to peripheral tolerance through interaction with and deletion of self-reactive CD4+ T cells. However, AIRE’s role in the periphery is likely more multi-faceted than in the thymus. We recently identified AIRE expression in tumor associated macrophages (TAMs), which are known to inhibit anti-tumor immune responses. While Aire-expressing tumor associated macrophages (aTAMs) were only recently discovered by our group, prior work implicates AIRE in inhibiting anti-tumor immunity. Recently available tools to study AIRE in mice have facilitated investigation of peripheral AIRE expression and aTAMs. We have found aTAMs in several common solid tumor models expressing common macrophage markers (CD11b, F4/80, and CD64) by both flow cytometry and mass cytometry (CyTOF). Additionally, interrogation of several public human RNA-seq datasets supports AIRE expression in tumor resident myeloid cell types. This preliminary data together with the therapeutic potential for targeting aTAMs to improve cancer immunotherapy make this a population deserving of thorough functional investigation. This proposal will test the hypothesis that aTAMs are an immunosuppressive, pro-tumoral cell population. Aim 1 of this proposal will define the phenotypic, transcriptional, and epigenetic profiles of aTAMs. Aim 2 will determine the mechanism(s) driving induction of AIRE expression in aTAMs. Aim 3 will identify the role of aTAMs in regulating local and systemic immune responses during anti-tumor immunity. This research approach will be carried out using a variety of methods including single cell analysis via RNA-seq, CyTOF, flow cytometry, and ATAC-seq, ex vivo co-cultures, and in vivo assays utilizing novel genetic mouse models. These proposed studies will be the first characterization of AIRE expression in any tumor resident immune cells and will further establish our understanding of the function of peripheral AIRE- expressing cell types. This could result in the discovery of novel pathways relevant to therapeutic resistance and further our understanding of global AIRE function. Translationally, this work may identify novel perturbations to improve patient responses to immunotherapy. This research project and fellowship training will be conducted at a top-funded research institution, the University of California, San Francisco (UCSF), in the laboratories of Dr. Matthew Spitzer, Dr. Lewis Lanier, and Dr. James Gardner with expert mentorship from Dr. Matthew (Max) Krummel. Dr. Lanier has made extensive foundational discoveries in immune cell biology. Dr. Spitzer has expertise in systems immunology and single cell methods. Dr. James Gardner has expertise in the study of peripheral AIRE and mouse model generation. Dr. Max Krummel has expertise in tumor myeloid cell biology and cancer immunotherapies. Overall, this facility and team provide a rich training environment for completion of this research and development of professional skills necessary for a career in academic research.

项目摘要/摘要自身免疫调节剂基因（AIR）通过促进自反应性T细胞的胸腺缺失来防止自身免疫性。虽然大多数在胸腺中的研究二，但Aire也以次级淋巴器官的形式表达通过与自反应性CD4+ T细胞的相互作用和缺失来促进外围耐受性。然而， Aire在外围的角色可能比胸腺更多。我们最近确定了艾尔肿瘤相关巨噬细胞（TAM）中的表达，已知会抑制抗肿瘤免疫复杂。虽然我们小组最近才发现了表达AIRE肿瘤相关的巨噬细胞（ATAM），但先前的工作实现AIRE抑制抗肿瘤免疫。最近可用于研究小鼠AIRE的工具促进了周围AIRE表达和ATAM的研究。我们已经在几个共同的地方找到了ATAM 通过两个流式细胞仪表达常见巨噬细胞标记（CD11b，F4/80和CD64）的实体瘤模型和质量细胞仪（细胞）。此外，对几个公共人类RNA-seq数据集的询问肿瘤居民粒状细胞类型中的AIR表达。此初步数据与疗法一起靶向ATAM改善癌症免疫疗法的潜力使得该人口应有彻底的功能投资。该提议将检验以下假设：ATAM是一种免疫抑制，亲肿瘤细胞种群。该提案的目标1将定义表型，转录和表观遗传 ATAMS的概况。 AIM 2将确定ATAM中AIR表达的驱动机制。目的 3将确定ATAM在抗肿瘤免疫期间确定局部和全身免疫复杂的作用。这种研究方法将使用多种方法进行，包括通过RNA-Seq，包括单细胞分析，使用新型遗传小鼠的体内共培养和体内共培养和体内测定型号。这些提出的研究将是任何肿瘤中AIR表达的第一个表征居民免疫小球，将进一步建立我们对外围aire的功能的理解表达细胞类型。这可能导致发现与热电阻有关的新型途径进一步我们对全球AIR功能的理解。翻译上，这项工作可以识别出新颖的扰动改善患者对免疫疗法的反应。这个研究项目和奖学金培训将是在加利福尼亚大学旧金山大学（UCSF）的一家资金资助的研究机构（UCSF）进行 Matthew Spitzer博士，Lewis Lanier博士和James Gardner博士的实验室，博士的专家心态马修（马克斯）克鲁梅尔。 Lanier博士在免疫细胞生物学方面取得了广泛的基础发现。博士 Spitzer在系统免疫学和单细胞方法方面具有专业知识。詹姆斯·加德纳博士在周围AIRE和小鼠模型产生的研究。 Max Krummel博士在肿瘤髓样细胞方面具有专业知识生物学和癌症免疫疗法。总体而言，该设施和团队为完成这项研究和发展学术研究所需的专业技能的研究和发展。