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

• 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
• 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

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.

项目摘要/摘要 白介素1b（IL-1b）是一种促炎性细胞因子，在小鼠和人类癌症中作用矛盾。这 细胞因子通过促进血管生成来增强肿瘤的生长，并由IL-1B介导的慢性炎症CAN 诱导致癌。同时，IL-1信号传导增强了自适应免疫系统，极化CD4+ T细胞朝着T辅助型1和17谱系，并增强CD8+ T细胞的效应函数以改进 肿瘤细胞杀死。一项大型临床试验发现，抗IL-1B治疗显着降低了肿瘤的发病率 人类强调了IL-1信号传导对人类健康的影响。 IL-1信号传导均由两个 受体拮抗剂（IL-1RA）和非信号诱饵受体（IL-1R2）。 IL-1RA在有机体一级起作用 抑制全身注射，而IL-1R2被认为会减弱组织中的局部注入。 使用RNA测序，我们已经确定了高度活化的IL-1R2+调节T细胞（Tregs）的群体 来自小鼠和人类的健康皮肤和肿瘤样品。 Treg是炎症的关键补充 组织，但是肿瘤浸润的Treg可以抑制适应性免疫学以促进癌症的生长。但是， 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 导致小鼠的肿瘤生长增加，表明IL-1信号传导增强了Treg激活。这个建议 将测试IL-1R2的TREG表达是否通过细胞固有方式减弱其激活 中和局部IL-1B。首先，我们将定义影响小鼠TREG的IL-1R2表达的因素， 人类（目标1）。然后，我们将研究IL-1R2对肿瘤浸润Treg的功能作用（AIM 2）。 最后，我们将确定是否可以将IL-1R2用作选择性重复肿瘤中的Treg的目标 增强抗肿瘤免疫力（AIM 3）。该提案不仅会扩大我们对IL-1信号传导的理解 Tregs，但也可能为癌症免疫疗法建立新的方法。 该研究策略将与制定申请人的全面培训计划一起进行 作为学术身体科学家的职业。培训将包括技术的结构化和严格的心态 通过常规的物理科学家赞助商的技能和实验设计 一对一的和实验室会议，课程，半岛，期刊俱乐部和免疫学部门活动。这 研究和培训将在加利福尼亚大学旧金山分校举行，该大学提供了极好的 免疫学研究环境以及杰出的生物医学科学研究生教育。