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.

项目总结/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。的 细胞因子通过促进血管生成来增强肿瘤生长，IL-1B介导的慢性炎症可以 诱发致癌作用。与此同时，IL-1信号转导支持适应性免疫系统，极化CD 4 + T细胞向辅助性T细胞1型和17型谱系分化，并增强CD 8 + T细胞的效应功能，以提高 肿瘤细胞杀伤一项大型临床试验发现，抗IL-1B治疗显著降低了 人类，突出了IL-1信号对人类健康的影响。IL-1信号传导受到两种调节， 受体拮抗剂（IL-1 RA）和非信号转导诱饵受体（IL-1 R2）。IL-1 RA在生物体水平起作用， IL-1 R2抑制全身性炎症，而IL-1 R2被认为减弱组织中的局部炎症。 使用RNA测序，我们已经确定了一个高度活化的IL-1 R2+调节性T细胞（Tcells）群体。 在健康皮肤和肿瘤样本中发现的。甲状腺素是炎症的关键抑制因子， 组织，但肿瘤浸润THBE可以抑制适应性免疫，促进癌症生长。但 IL-1 R2在癌症和Treg生物学中的功能还不清楚。在我们的手中，删除T细胞上的IL-1 R2 导致小鼠肿瘤生长增加，表明IL-1信号转导增强Treg活化。这项建议 将测试IL-1 R2的Treg表达是否以细胞内在方式减弱它们的激活， 中和局部IL-1B。首先，我们将确定诱导小鼠TCFs上IL-1 R2表达的因素， 人类（目标1）。然后，我们将研究IL-1 R2对肿瘤浸润性T细胞的功能作用（目的2）。 最后，我们将确定IL-1 R2是否可以用作选择性地消耗肿瘤中的T细胞的靶点， 增强抗肿瘤免疫力（目标3）。该提议不仅将拓宽我们对IL-1信号转导的理解， 但也可能为癌症免疫治疗建立一种新的方法。 这项研究战略将与全面的培训计划一起进行，以发展申请人的 作为一名学术物理学家的职业生涯。培训将包括在技术方面有条理和严格的指导。 技能和实验设计，从一个高素质的医生，科学家赞助商，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。的 研究和培训将在加州大学旧金山弗朗西斯科进行，该大学提供了一个优秀的 免疫学的研究环境以及生物医学科学的优秀研究生教育。