Control of regulatory T cells by IL-17 in colorectal cancer

项目概要/摘要： IL-17家族细胞因子促进炎症，从而驱动结直肠肿瘤的发展， 最终导致结直肠癌（CRC）。到目前为止，基本机制主要归因于 IL-17在骨髓细胞募集中的作用IL-17是否也向适应性免疫细胞，特别是CD 4+细胞发出信号 调节性T细胞（Tcells），以及这种信号传导是否在结直肠肿瘤发生中起作用，仍然未知。 我们的初步研究表明，靶向消融Treg细胞上的IL-17信号通路可增加结肠肿瘤的发生， 在小鼠中的发展，证明了以前未知的IL-17在CRC中的保护作用。我们还发现 IL-17直接抑制肿瘤中的Treg积累。此外，IL-17抑制促进细胞凋亡的基因的表达。 Treg迁移、增殖和免疫抑制功能。重要的是，这些影响仅在 肿瘤浸润性T细胞，表明IL-17对T细胞的位点特异性抑制。根据这一概念，只有 肿瘤浸润性T细胞表达IL-17 RC和IL-17 A、C和F细胞因子的RE共受体。刺激 用IL-6和IL-1β（两种在肿瘤环境中丰富的细胞因子）刺激，上调IL-17 RE， 这表明肿瘤微环境使TcB对IL-17介导的抑制敏感。另 此外，我们还发现IL-17可通过信号转导下调肿瘤细胞CXCL 9和10的表达， 通过其同源受体CXCR 3发出信号以吸引CD 8 + CTL至肿瘤。这些初步结果 支持我们的假设，即IL-17通过两种相反的机制调节结肠直肠肿瘤的发展： 1)IL-17直接抑制否则将抑制癌症免疫监视的TcR;和 通过下调CXCL 9/10的产生将CD 8 + CTL吸引到肿瘤环境中。鉴于 Th 17细胞和Th 17细胞在肿瘤发展中的关键作用，沿着与Th 17细胞相关的知识空白， 为了研究IL-17对Treg生物学的影响，我们提出了以下研究：1）阐明IL-17如何直接介导Treg的生物学功能， 2）阐明IL-17介导的肿瘤细胞凋亡的分子机制， 3）探究IL-17如何通过调节CXCL 9/10抑制T细胞吸引，以及 测试IL-17-Treg回路在结直肠肿瘤发展和治疗中的重要性。这些调查将 为IL-17影响结直肠肿瘤发生的机制提供了新的见解，并指导了 本发明涉及用于治疗人类CRC的新疗法的发明和用途。例如，基于IL-1的作用， 在抑制CD 8 + CTL对肿瘤的吸引方面，我们可以使用目前可用的IL-17 A和IL-17 RA抗体 作为癌症免疫治疗的辅助剂。然而，对于富含IL-17和THBG的肿瘤， 中和IL-17可能进一步增强Treg的免疫抑制并使治疗结果恶化。解耦 IL-17-Treg相互作用对于自身免疫和细菌感染的治疗也可能是重要的，并且将促进IL-17-Treg相互作用。 在以后的研究中加以探讨。

Project Summary/Abstract: IL-17 family cytokines promote inflammation that drives the development of colorectal neoplasia, which eventually lead to colorectal cancer (CRC). Thus far, the underlying mechanism has largely been attributed to IL-17’s role in myeloid cell recruitment. Whether IL-17 also signals to adaptive immune cells, in particular CD4+ regulatory T cells (Tregs), and whether this signaling plays a role in colorectal tumorigenesis, remains unknown. Our preliminary studies show that targeted ablation of IL-17 signaling on Treg cells increased colonic tumor development in mice, demonstrating a previously unknown protective role of IL-17 in CRC. We also found that IL-17 directly inhibits Treg accumulation in tumors. Further, IL-17 inhibits the expression of genes that facilitate Treg migration, proliferation, and immune suppressive function. Importantly, these effects are only observed in tumor-infiltrating Tregs, suggesting a site-specific inhibition of Tregs by IL-17. Consistent with this notion, only tumor-infiltrating Tregs express IL-17RC and RE – co-receptors for IL-17A, C, and F cytokines. Stimulation of Tregs with IL-6 and IL-1β, two cytokines that are abundant in the tumor environment, upregulates IL-17RE, suggesting that the tumor microenvironment renders Tregs susceptible to IL-17-mediated inhibition. On the other hand, we also found that IL-17 signals to tumor cells to downregulate the expression of CXCL9 and 10, which signal through their cognate receptor CXCR3 to attract CD8+ CTLs to the tumor. These preliminary findings support our hypothesis that IL-17 regulates colorectal tumor development through two opposing mechanisms: 1) IL-17 directly inhibits Tregs that would otherwise suppress cancer immunosurveillance; and 2) IL-17 inhibits the attraction of CD8+ CTLs into the tumor environment by downregulating CXCL9/10 production. Given the critical roles of both Tregs and Th17 cells in tumor development, along with the knowledge gap relating to the impact of IL-17 on Treg biology, we propose the following studies: 1) Delineate how IL-17 mediates direct inhibition of Tregs in colorectal tumors; 2) Elucidate the molecular mechanism(s) underlying IL-17-mediated inhibition of Tregs; and 3) Interrogate how IL-17 inhibits T cell attraction through the regulation of CXCL9/10, and test the importance of IL-17-Treg circuitry in colorectal tumor development and therapy. These investigations will provide new insights into the mechanisms by which IL-17 impacts colorectal tumorigenesis, as well as guide the invention and use of novel therapies for the treatment of CRC in humans. For example, based on a role for IL- 17 in inhibiting CD8+ CTL attraction to tumor, we may employ currently available IL-17A and IL-17RA antibodies as adjuvant agents for cancer immunotherapy. However, for tumors that are abundant with IL-17 and Tregs, neutralizing IL-17 may further enhance Treg’s immune suppression and worsen treatment outcome. Uncoupling IL-17-Treg interactions may also be important for the treatment of autoimmunity and bacterial infections, and will be explored in subsequent studies.