The role of decoy receptor IL-1R2 in Treg biology and anti-tumor immunity

诱饵受体IL-1R2在Treg生物学和抗肿瘤免疫中的作用

基本信息

批准号：
10606139
负责人：
Ireneusz Habrylo
金额：
$ 5.27万
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606139
关键词：
Adaptive Immune System Affect Animal Model Attenuated Big Data Biological Assay Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CRISPR/Cas technology California Cell physiology Cell surface Cells Cellular biology Chronic Clinical Trials Complex Data Environment Event Experimental Designs Genetic Transcription Graduate Education Growth Health Human IL1R1 gene IL1R2 gene Immune Immune Evasion Immunology Incidence Infiltration Inflammation Inflammatory Interleukin-1 Interleukin-1 Receptors Interleukins Journals Kinetics Label Malignant Neoplasms Mediating Mentorship Modeling Mus Myelogenous Myeloid Cells Organism Pathway interactions Physicians Population Productivity Qualifying Receptor Signaling Regulatory T-Lymphocyte Reporter Reporting Research Role Sampling San Francisco Science Scientist Signal Transduction Skin Structure System T cell response T-Cell Activation T-Cell Receptor Technical Expertise Testing Time Tissues Training Transgenic Organisms Tumor Immunity Tumor Markers Universities adaptive immunity anakinra angiogenesis antagonist anti-PD-1 anti-tumor immune response cancer immunotherapy cancer infiltrating T cells cancer therapy carcinogenesis career cell killing checkpoint therapy cytokine experimental study improved inhibitor meetings melanoma neoplastic cell new therapeutic target novel strategies novel therapeutic intervention permissiveness protein expression receptor response single-cell RNA sequencing systemic inflammatory response transcriptome sequencing tumor tumor growth tumor microenvironment

项目摘要

Project Summary/Abstract Interleukin-1B (IL-1B) is a pro-inflammatory cytokine with conflicting roles in mouse and human cancers. The cytokine enhances tumor growth by promoting angiogenesis, and chronic inflammation mediated by IL-1B can induce carcinogenesis. At the same time, IL-1 signaling bolsters the adaptive immune system, polarizing CD4+ T cells toward T helper type 1 and 17 lineages and enhancing the effector function of CD8+ T cells to improve tumor cell killing. A large clinical trial found that anti-IL-1B treatment significantly reduced tumor incidence in humans, highlighting the effect of IL-1 signaling on human health. IL-1 signaling is well-regulated by both a receptor antagonist (IL-1RA) and a non-signaling decoy receptor (IL-1R2). IL-1RA acts at the organism level to suppress systemic inflammation, while IL-1R2 is thought to attenuate local inflammation in tissues. Using RNA sequencing, we have identified a population of highly activated IL-1R2+ regulatory T cells (Tregs) in healthy skin and tumor samples from mice and humans. Tregs are critical suppressors of inflammation in tissues, but tumor infiltrating Tregs can dampen adaptive immunity to promote cancer growth. However, the function of IL-1R2 in cancer and Treg biology is not well understood. In our hands, deleting IL-1R2 on Tregs led to increased tumor growth in mice, suggesting that IL-1 signaling enhances Treg activation. This proposal will test whether Treg expression of IL-1R2 attenuates their activation in a cell intrinsic fashion by neutralizing local IL-1B. First, we will define the factors that induce IL-1R2 expression on Tregs in mice and humans (Aim 1). We will then investigate the functional role of IL-1R2 on tumor infiltrating Tregs (Aim 2). Lastly, we will determine whether IL-1R2 can be used as a target to selectively deplete Tregs in tumors and bolster anti-tumor immunity (Aim 3). The proposal will not only broaden our understanding of IL-1 signaling in Tregs but may also establish a new approach for cancer immunotherapy. This research strategy will be conducted alongside a comprehensive training plan to develop the applicant’s career as an academic physician-scientist. Training will include structured and rigorous mentorship in technical skills and experimental design from a highly qualified physician-scientist sponsor, carried out through regular one-on-one and lab meetings, courses, seminars, journal clubs, and immunology department events. The research and training will take place at the University of California, San Francisco, which provides an excellent research environment for immunology alongside an outstanding graduate education in biomedical sciences.

项目概要/摘要白细胞介素-1B (IL-1B) 是一种促炎细胞因子，在小鼠和人类癌症中具有相互冲突的作用。细胞因子通过促进血管生成来增强肿瘤生长，而 IL-1B 介导的慢性炎症可以同时，IL-1 信号增强适应性免疫系统，极化 CD4+。 T 细胞朝向 1 型和 17 型辅助 T 谱系并增强 CD8+ T 细胞的效应功能，以改善一项大型临床试验发现，抗 IL-1B 治疗可显着降低肿瘤发生率。人类，强调 IL-1 信号传导对人类健康的影响受到两者的良好调节。受体拮抗剂（IL-1RA）和非信号诱饵受体（IL-1R2）在生物体水平上发挥作用。抑制全身炎症，而 IL-1R2 被认为可以减轻组织的局部炎症。通过 RNA 测序，我们鉴定出了一群高度激活的 IL-1R2+ 调节性 T 细胞 (Treg) 在小鼠和人类的健康皮肤和肿瘤样本中，Tregs 是炎症的关键抑制因子。组织，但肿瘤浸润的 Tregs 可以抑制适应性免疫，促进癌症生长。 IL-1R2 在癌症和 Treg 生物学中的功能尚不清楚。在我们手中，删除 Tregs 上的 IL-1R2。导致小鼠肿瘤生长增加，表明 IL-1 信号增强了 Treg 激活。将测试 IL-1R2 的 Treg 表达是否以细胞内在方式减弱其激活首先，我们将定义诱导小鼠 Treg 上 IL-1R2 表达的因素。然后，我们将研究 IL-1R2 对肿瘤浸润性 Tregs 的功能作用（目标 2）。最后，我们将确定IL-1R2是否可以作为靶点选择性地消耗肿瘤中的Tregs并增强抗肿瘤免疫力（目标 3）。该提案不仅将拓宽我们对 IL-1 信号传导的理解。 Tregs 还可能为癌症免疫治疗建立一种新方法。该研究策略将与全面的培训计划一起进行，以培养申请人的能力作为一名学术医师科学家的职业生涯，培训将包括结构化和严格的技术指导。来自高素质医师科学家赞助商的技能和实验设计，通过定期进行一对一和实验室会议、课程、研讨会、期刊俱乐部和免疫学系活动。研究和培训将在旧金山加利福尼亚大学进行，该大学提供了优秀的免疫学研究环境以及出色的生物医学研究生教育。