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

• 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
• 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

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家族细胞因子促进感染，驱动着结直肠肿瘤的发展，这 最终导致结直肠癌（CRC）。那远，基本机制主要归因于 IL-17在髓样细胞募集中的作用。 IL-17是否也向自适应免疫细胞发信号，特别是CD4+ 调节性T细胞（Tregs），以及该信号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，针对Treg细胞上IL-17信号传导的靶向消融会增加结肠肿瘤 在小鼠中发育，证明了IL-17在CRC中的先前未知的保护作用。我们还发现 IL-17直接抑制肿瘤中的Treg积累。此外，IL-17抑制了促进的基因的表达 Treg迁移，增殖和免疫抑制功能。重要的是，这些影响仅在 肿瘤浸润的Treg，表明IL-17对TREG的位点特异性抑制作用。与这个概念一致 肿瘤浸润的Treg表达IL-17RC和RE - IL-17A，C和F细胞因子的共受体。刺激 具有IL-6和IL-1β的Treg，两种在肿瘤环境中丰富的细胞因子上调IL-17RE， 表明肿瘤微环境使Treg易受IL-17介导的抑制作用。另一方面 手，我们还发现肿瘤细胞的IL-17信号下调了CXCL9和10的表达，这 通过其同源受体CXCR3发出信号，吸引CD8+ CTL到肿瘤。这些初步发现 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产生，CD8+ CTL的吸引到肿瘤环境中。鉴于 Tregs和Th17细胞在肿瘤发育中的关键作用，以及与 IL-17对Treg生物学的影响，我们提出以下研究：1）描述IL-17媒体如何指导 抑制结直肠肿瘤中的Treg； 2）阐明IL-17介导的基础的分子机制 抑制tregs； 3）询问IL-17如何通过调节CXCL9/10抑制T细胞的吸引力，并且 测试IL-17-Treg电路在结直肠肿瘤发育和治疗中的重要性。这些调查会 提供有关IL-17影响结直肠肿瘤发生的机制的新见解，并指导 发明和使用新型疗法用于人类CRC的治疗。例如，基于IL的角色 17在抑制CD8+ CTL吸引肿瘤时，我们可能会采用当前可用的IL-17A和IL-17RA抗体 作为癌症免疫疗法的可调剂。但是，对于IL-17和Tregs丰富的肿瘤， 中和IL-17可能会进一步增强Treg的免疫抑制和较差的治疗结果。解偶联 IL-17-Treg相互作用对于治疗自身免疫和细菌感染也可能很重要，并且将会 在随后的研究中进行探讨。