Interleukin-35 and the tumor microenvironment

项目总结 肿瘤微环境中的抑制机制是有效抗肿瘤的主要障碍 豁免权。虽然在临床试验中报道了对各种肿瘤类型的显著疗效，但抑制作用 受体阻断，很明显，额外的抑制机制将需要有针对性地实质性地 改善大多数肿瘤类型的治疗结果。调节性T细胞(Tregs)是有效的抗肿瘤抑制因子 豁免权。尽管靶向Treg消融导致多种人类癌症模型的肿瘤迅速缩小， 这不是一个可行的治疗方法，因为随后会出现严重的自身免疫和炎症。 后果。因此，更有针对性地限制肿瘤微环境中的Treg活性 此外，还需要深入了解它们的作用机制。尽管Tregs使用多个 控制T细胞功能的抑制机制，目前尚不清楚哪些机制在肿瘤微环境中占主导地位 因此可能成为癌症的有效治疗靶点。白介素35(IL35)是一种Ebi3/IL12a异源二聚体，是一种 由Tregs产生的抑制性细胞因子，是T细胞增殖和功能的有效抑制因子。Treg派生的 IL35还可以促进诱导的调节性T细胞群的发展，这种T细胞群通过IL35抑制 (ITr35)，这反过来又可以促进抑制性的肿瘤内环境。然而，生理上的影响 而IL35在肿瘤微环境中的作用机制很大程度上还不清楚。在这场竞争中 更新申请，我们将确定IL35是如何调节肿瘤微环境的。 目的1：研究IL35+Tregs在肿瘤微环境中的作用和去向。使用Ebi3记者， 我们将确定Tregs产生IL35的生理重要性 以及Ebi3+与Ebi3-Tregs在肿瘤中的作用和命运。 目的2：检测IL35对肿瘤微环境中CD8+T细胞的影响。使用Ebi3 ，我们将确定Treg来源的IL35对CD8+T细胞功能和命运的影响 肿瘤。 这个项目将对我们对生理重要性的理解和 IL-35在肿瘤微环境中的作用机制鉴于我们发现了IL35并拥有 许多独特的工具来探索它的功能，我们处于最好的位置来进行这项研究。

PROJECT SUMMARY Inhibitory mechanisms within the tumor microenvironment represent major barriers to effective antitumor immunity. Although striking efficacy in a variety of tumor types has been reported in clinical trails with inhibitory receptor blockade, it's clear that additional inhibitory mechanisms will need to be targeted to substantially improve therapeutic outcome in most tumor types. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor immunity. Although targeted Treg ablation results in rapid tumor shrinkage in multiple models of human cancer, this is not a viable therapeutic approach due to the subsequent severe autoimmune and inflammatory consequences. Thus more targeted approaches to limit Treg activity selectively in the tumor microenvironment are needed, along with in depth understanding of their mechanism of action. Although Tregs use multiple inhibitory mechanisms to control T cell function, it is unclear which are dominant in the tumor microenvironment and thus may be viable therapeutic targets in cancer. Interleukin-35 (IL35), an Ebi3/Il12a heterodimer, is an inhibitory cytokine produced by Tregs that is a potent suppressor of T cell proliferation and function. Treg-derived IL35 can also promote the development of an induced regulatory T cell population that suppresses via IL35 (iTr35), which in turn can contribute to the suppressive intratumoral milieu. However, the physiological impact and mechanism of action of IL35 within the tumor microenvironment are largely unknown. In this competitive renewal application, we will determine how IL35 modulates the tumor microenvironment. AIM 1: Dissecting the function and fate of IL35+ Tregs in the tumor microenvironment. Using Ebi3 reporter, conditional and linage tracing mice, we will determine the physiological importance of IL35 production by Tregs in tumors and the role and fate of Ebi3+ versus Ebi3– Tregs. AIM 2: Determining the impact of IL35 on CD8+ T cells within the tumor microenvironment. Using Ebi3 conditional mice, we will determine the impact of Treg-derived IL35 on the function and fate of CD8+ T cells in tumors. This project will have a significant impact of our understanding of the physiological importance and mechanism of action of IL35 in the tumor microenvironment. Given that we discovered IL35 and have many unique tools to probe its function, we are in the best position to conduct this research.