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

项目摘要/摘要 白介素1B(IL-1B)是一种促炎细胞因子，在小鼠和人类癌症中的作用相互冲突。这个 细胞因子通过促进血管生成促进肿瘤生长，IL-1B介导的慢性炎症可以 诱发致癌。同时，IL-1信号支持适应性免疫系统，极化CD4+ T细胞向辅助性T细胞1型和17型转化，增强CD8+T细胞的效应功能 杀灭肿瘤细胞。一项大型临床试验发现，抗IL-1B治疗显著降低了 强调了IL-1信号对人类健康的影响。IL-1信号受两种受体的良好调节 受体拮抗剂(IL-1RA)和非信号诱骗受体(IL-1R2)。IL-1RA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中的局部炎症。 使用RNA测序，我们已经确定了一组高度激活的IL-1R2+调节性T细胞(Treg) 在来自老鼠和人类的健康皮肤和肿瘤样本中。树突状细胞是炎症的关键抑制因子 组织，但肿瘤浸润性Tregs可抑制适应性免疫，促进癌症生长。然而， IL-1R2在肿瘤和Treg生物学中的作用尚不清楚。在我们手中，删除树上的IL-1R2 导致小鼠肿瘤生长增加，表明IL-1信号增强Treg激活。这项建议 将测试IL-1R2的Treg表达是否通过以下方式以细胞内在方式减弱其激活 中和局部IL-1B。首先，我们将确定诱导小鼠树突状细胞IL-1R2表达的因素和 人类(目标1)。然后我们将研究IL-1R2在肿瘤浸润性树突状细胞中的功能作用(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Treg和 增强抗肿瘤免疫力(目标3)。这项提议不仅将拓宽我们对IL-1信号转导途径的理解 Tregs还可能建立一种新的癌症免疫治疗方法。 这项研究战略将与全面的培训计划一起进行，以发展申请者的 作为一名学术内科医生兼科学家的职业。培训将包括有组织和严格的技术指导 技能和实验设计来自高资质的医生-科学家赞助商，通过常规 一对一和实验室会议、课程、研讨会、杂志俱乐部和免疫学系活动。这个 研究和培训将在加州大学旧金山分校进行，该校提供了极好的 免疫学的研究环境，以及在生物医学科学方面出色的研究生教育。

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.