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：
10619017
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/10619017
关键词：
Ablation Acceleration Adjuvant Adoptive Transfer Affect Anti-Inflammatory Agents Antibodies Autoimmunity B-Lymphocytes Bacterial Infections CCR6 gene CD8B1 gene CXC chemokine receptor 3 CXCL9 gene CXCR3 gene Cell Communication Cell Survival Cell physiology Cells Cellular biology Colon Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Development Environment Epithelial Cells FOXP3 gene Family Family member Fibroblasts Gene Expression Genetic Transcription Glucose Glycolysis Human IL17 gene IL2RA gene Immune Immune Cell Suppression Immunologic Surveillance Immunosuppression Immunotherapy Infiltration Inflammation Inflammatory Interleukin-1 beta Interleukin-10 Interleukin-2 Interleukin-6 Investigation Knowledge Malignant Neoplasms Mediating Membrane Molecular Mus Myeloid Cells PDPK1 gene PIK3CG gene Phase Play Predisposition Prevention strategy Production Proliferating 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 cancer immunotherapy cancer initiation cancer prevention cell motility 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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High glucose promotes regulatory T cell differentiation.

DOI：
10.1371/journal.pone.0280916
发表时间：
2023
期刊：
PLOS ONE
影响因子：
3.7
作者：
Pitmon, Elise;Meehan, Eileen Victoria;Ahmadi, Elham;Adler, Adam J.;Wang, Kepeng
通讯作者：
Wang, Kepeng

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