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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Treg的积累。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。

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

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.