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

IL-17 在结直肠癌中对调节性 T 细胞的控制

基本信息

批准号：
10414125
负责人：
Kepeng Wang
金额：
$ 36.76万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414125
关键词：
Ablation Adjuvant Adoptive Transfer Affect Anti-Inflammatory Agents Antibodies Autoimmunity B-Lymphocytes Bacterial Infections Biology CCR6 gene CD8B1 gene CXC chemokine receptor 3 CXCL9 gene CXCR3 gene Cells Colon Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Development Environment Epithelial Cells FOXP3 gene Family Family member Fibroblasts Gene Expression Genetic Transcription Glucose Glycolysis Human IL2RA gene Immune Immunologic Surveillance Immunosuppression Immunotherapy Infiltration Inflammation Inflammatory Interleukin-1 beta Interleukin-10 Interleukin-17 Interleukin-2 Interleukin-6 Investigation Knowledge Lead Malignant Neoplasms Mediating Membrane Molecular Mus Myeloid Cells PDPK1 gene Phase Play Prevention strategy Production Regulation Regulatory T-Lymphocyte Reporting Role Signal Pathway Signal Transduction Site Specimen Stat5 protein T-Lymphocyte Testing Transforming Growth Factor beta Treatment outcome Tumor Immunity Work adaptive immunity anticancer activity base cancer immunotherapy cancer initiation cancer prevention chemokine colon tumorigenesis colorectal cancer treatment cytokine design improved insight interleukin-17C invention migration mouse model mutant neoplastic cell neutrophil novel novel therapeutics phosphoinositide-3,4,5-triphosphate prevent receptor recruit treatment strategy tumor tumor microenvironment tumorigenesis

项目摘要

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.

项目摘要/摘要： IL-17 家族细胞因子会促进炎症，从而导致结直肠肿瘤的发展，从而导致结直肠肿瘤的发生。最终导致结直肠癌（CRC）迄今为止，其潜在机制主要归因于。 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 CD4+）发出信号。调节性 T 细胞 (Treg) 以及这种信号传导是否在结直肠肿瘤发生中发挥作用仍不清楚。我们的初步研究表明，Treg 细胞上 IL-17 信号传导的靶向消除会增加结肠肿瘤的发生我们还发现，IL-17 在小鼠中的发育具有先前未知的保护作用。 IL-17 直接抑制肿瘤中 Treg 的积累，此外，IL-17 还抑制促进基因的表达。重要的是，这些效应仅在 Treg 迁移、增殖和免疫抑制功能中观察到。肿瘤浸润性 Tregs，表明 IL-17 对 Tregs 具有位点特异性抑制作用，仅与这一概念一致。肿瘤浸润性 Tregs 表达 IL-17RC 和 RE——IL-17A、C 和 F 细胞因子的共同受体。具有 IL-6 和 IL-1β（肿瘤环境中丰富的两种细胞因子）的 Tregs 上调 IL-17RE，表明肿瘤微环境使 Tregs 容易受到 IL-17 介导的抑制作用。另一方面，我们还发现 IL-17 向肿瘤细胞发出信号，下调 CXCL9 和 10 的表达，这这些初步发现通过其同源受体 CXCR3 发出信号将 CD8+ CTL 吸引到肿瘤。支持我们的假设，即 IL-17 通过两种相反的机制调节结直肠肿瘤的发展： 1) IL-17 直接抑制 Tregs，否则会抑制癌症免疫监视；2) IL-17 抑制；通过下调 CXCL9/10 的产生将 CD8+ CTL 吸引到肿瘤环境中。 Tregs 和 Th17 细胞在肿瘤发展中的关键作用，以及与为了了解 IL-17 对 Treg 生物学的影响，我们提出以下研究： 1) 描述 IL-17 如何直接介导结直肠肿瘤中 Tregs 的抑制；2) 阐明 IL-17 介导的分子机制抑制 Tregs；以及 3) 研究 IL-17 如何通过调节 CXCL9/10 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。为 IL-17 影响结直肠肿瘤发生的机制提供新的见解，并指导例如，基于IL-的作用，发明和使用治疗人类CRC的新疗法。 17 为了抑制 CD8+ CTL 对肿瘤的吸引力，我们可以使用目前可用的 IL-17A 和 IL-17RA 抗体作为癌症免疫治疗的佐剂，然而，对于富含 IL-17 和 Tregs 的肿瘤，中和 IL-17 可能会进一步增强 Treg 的免疫抑制并恶化治疗结果。 IL-17-Treg 相互作用对于自身免疫和细菌感染的治疗也可能很重要，并且将在后续的研究中进行探讨。