Dissecting the Myeloid-Th17 axis in the pathogenesis of Colitis-associated Colorectal Cancer

剖析结肠炎相关结直肠癌发病机制中的骨髓-Th17 轴

• 批准号: 10581383
• 负责人: Awalpreet Singh Chadha
• 金额: $ 14.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581383
• 关键词: ARG2 gene; Address; Attenuated; Automobile Driving; Azoxymethane; CD4 Positive T Lymphocytes; Cancer Etiology; Cell Differentiation process; Cell Maintenance; Cells; Cessation of life; Chronic; Colitis associated colorectal cancer; Colon; Colonic Neoplasms; Colonic inflammation; Colorectal Cancer; Complex; Development; Digestive System Disorders; Dimerization; Disease; Disease Progression; Event; Family; Feedback; Foundations; Gene Expression; Genes; Growth; Heterogeneity; Human Herpesvirus 4; IL12B gene; IL17 gene; ITGAM gene; Immune; Immune checkpoint inhibitor; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-12; Interleukins; Intervention; Invaded; Kinetics; Link; Macrophage; Maintenance; Mediating; Mediator; Molecular; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Play; Population; Process; Production; Prognosis; Resistance; Risk Factors; Role; Signal Transduction; Source; T-Lymphocyte; Testing; Therapeutic; Tumor Promotion; Tumor-associated macrophages; United States; Vascular Endothelial Growth Factors; Work; angiogenesis; chronic inflammatory disease; colon carcinogenesis; colorectal cancer progression; cytokine; design; dextran sulfate sodium induced colitis; gut inflammation; improved; insight; monocyte; mortality; neutrophil; novel; novel therapeutic intervention; prevent; programmed cell death ligand 1; rational design; recruit; response; single-cell RNA sequencing; synergism; treatment strategy; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic; γδ T cells

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality in the United States. Chronic intestinal inflammation is a major risk factor for the development and progression of sporadic and colitis- associated colorectal cancer (CAC). While the pathogenic effects of tumor-promoting inflammation are widely recognized, the mechanisms driving this process, including the cellular and molecular mediators are poorly understood. This has therapeutic implications especially in CRC where the currently available T-cell checkpoint inhibitors have a limited benefit. In preliminary studies, we used the azoxymethane/ dextran sulfate sodium model of inflammation-driven colon carcinogenesis that allows interrogation of the initiation-promotion events underpinning the development of CAC. We observed that compared to the surrounding non-tumor-bearing colon, the tumor microenvironment is enriched with tumor-infiltrating myeloid (TIM) cells, including neutrophils (PMNs), monocytes, and tumor-associated macrophages (TAMs). PMNs are the predominant population and are recruited through the Cxc-Cxcr2 axis while the monocytes/TAMs (M) appear to rely on the Cc-Ccr2 pathway. Both subsets express pro-inflammatory and immune-suppressive genes thereby suggesting their pro- tumorigenic role. Additionally, the tumor microenvironment has an increased abundance of interleukin (IL)-17 producing CD4+ T (Th17) and gamma-delta T cells. IL-17 is a pro-inflammatory cytokine that promotes CRC growth and increased expression is associated with poor prognosis. Previous studies indicate that TIMs promote Th17 development through the production of IL-23 (IL-23A/IL-12B heterodimer). However, our single-cell RNA sequencing studies revealed that while the PMNs expressed Il23a, they did not express Il12b thereby suggesting an inability to produce functional IL-23. Instead, the PMNs expressed Epstein-Barr virus-induced gene 3 (Ebi3) which has recently been shown to dimerize with IL-23A to form IL-39, a pro-inflammatory cytokine. We hypothesize that the myeloid-Th17 axis is critical for the maintenance of an inflammatory microenvironment that helps sustain CAC progression. We propose the existence of a feed-forward loop in the tumor microenvironment whereby the PMNs and M work synergistically to promote Th17 development, and the resulting IL-17, in turn, recruits and maintains more PMNs and M in the tumor thereby reinforcing an inflammatory microenvironment which fuels CAC progression. Mechanisms to disrupt this loop will be the focus of our proposal. Our first aim will attempt to define the role of TIMs in the pathogenesis of CAC by exploring the effects of blocking colonic recruitment of PMNs and M on tumor development (Aim IA) or their deletion in established tumors (Aim IB). In our second aim, we will explore the role of IL-39 as an alternative mechanism of Th17 development (Aim IIA) and assess its role in tumor development (Aim IIB), including the effects of cell-specific deletion of the Ebi3 in PMNs and CD4+T cells (Aim IIC). These studies will have implications in treatment strategies for patients with CAC and other immune-mediated diseases like inflammatory bowel disease.

结直肠癌（CRC）是美国癌症相关死亡的第二大原因。慢性 肠道炎症是散发性结肠炎和结肠炎发展和进展的主要危险因素， 结直肠癌（CAC）。虽然肿瘤促进炎症的致病作用是广泛的， 尽管已经认识到，驱动这一过程的机制，包括细胞和分子介质， 明白这具有治疗意义，特别是在CRC中，其中目前可用的T细胞检查点 抑制剂的益处有限。在初步研究中，我们使用氧化偶氮甲烷/葡聚糖硫酸钠模型 炎症驱动的结肠癌发生，允许询问启动-促进事件 支持CAC的发展。我们观察到，与周围的非肿瘤结肠相比， 肿瘤微环境富含肿瘤浸润性髓样（TIM）细胞，包括中性粒细胞（PMN）， 单核细胞和肿瘤相关巨噬细胞（TAM）。PMNs是主要人群， 通过Cxc-Cxcr 2轴募集，而单核细胞/TAM（TAM）似乎依赖于Cc-Ccr 2途径。 这两个亚群都表达促炎和免疫抑制基因，从而表明它们的促炎和免疫抑制基因。 致瘤作用此外，肿瘤微环境中白细胞介素（IL）-17丰度增加 产生CD 4 + T（Th 17）和γ-δ T细胞。IL-17是一种促进CRC的促炎细胞因子 生长和增加的表达与不良预后相关。以前的研究表明，TIM促进 通过产生IL-23（IL-23 A/IL-12 B异源二聚体）的Th 17发育。然而，我们的单细胞RNA 测序研究显示，虽然PMN表达IL 23 a，但它们不表达IL 12 b，从而表明 无法产生功能性IL-23。相反，PMNs表达EB病毒诱导的基因3（Ebi 3） 其最近显示与IL-23 A二聚化形成IL-39，一种促炎细胞因子。我们 假设髓系-Th 17轴对于维持炎性微环境至关重要， 有助于维持CAC进展。我们提出在肿瘤微环境中存在一个前馈回路 由此PMN和M β协同作用以促进Th 17的发育，而产生的IL-17，反过来， 募集并维持肿瘤中更多的中性粒细胞和巨噬细胞，从而加强炎症微环境 从而促进CAC的发展打破这一循环的机制将是我们提案的重点。我们的首要目标是 我们试图通过探讨结肠阻断剂的作用来确定TIMs在CAC发病机制中的作用， 在肿瘤发展（Aim IA）或在已建立的肿瘤中其缺失（Aim IB）中的PMN和M β募集。在 我们的第二个目标是探索IL-39作为Th 17发育的替代机制的作用（Aim IIA） 并评估其在肿瘤发展中的作用（Aim IIB），包括Ebi 3的细胞特异性缺失在肿瘤发生中的作用。 PMN和CD 4 +T细胞（Aim IIC）。这些研究将对以下患者的治疗策略产生影响： CAC和其他免疫介导的疾病，如炎症性肠病。