Mechanisms of cytokine driven tumor elicited inflammation in colorectal cancer

细胞因子驱动的肿瘤引发结直肠癌炎症的机制

• 批准号: 10461157
• 负责人: Sergei I. Grivennikov
• 金额: $ 45.19万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461157
• 关键词: 16S ribosomal RNA sequencing; Ablation; Adhesives; Animal Model; Anti-Inflammatory Agents; Antibiotics; Antibodies; Aspirin; Bacteria; Biological Markers; CDX2 gene; Cancer Biology; Cancer Etiology; Cell Communication; Cell Compartmentation; Cells; Cessation of life; Chronic; Colorectal Cancer; Common Neoplasm; Data; Deterioration; Development; Epithelial; First Name; Genetic; Germ-Free; Growth; Human; ITGAM gene; Immune; Immunology; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Interleukin-17; Knockout Mice; Lymphoid Cell; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Microbe; Mus; Myelogenous; Myeloid Cells; Nature; Normal tissue morphology; Oncogenes; Pathway interactions; Pharmaceutical Preparations; Population; Preventive; Preventive measure; Process; Production; Prognosis; Public Health; Receptor Cell; Risk; Role; Scheme; Shapes; Signal Transduction; Site; Solid; Solid Neoplasm; Stimulus; Surface; T-Lymphocyte; Taxonomy; Testing; Therapeutic; Time; Tumor Tissue; Tumor stage; Work; base; cancer cell; cancer risk; cell type; colon cancer patients; colorectal cancer progression; cytokine; early onset colorectal cancer; insight; interleukin-23; macrophage; microbial; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutics; receptor; recruit; transcription factor; tumor; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

PROJECT SUMMARY Tumor microenvironment (TME), particularly tumor-infiltrating inflammatory cells, is an essential component of tumorigenesis. Most of the solid tumors demonstrate a paradoxical ability to recruit immune cells and to upregulate inflammatory mediators which assist tumor progression. We first defined this process as “Tumor elicited inflammation” (TEI) and suggested that in colorectal cancer (CRC), TEI is induced early during the tumorigenesis, particularly because of the oncogene-induced, tumor specific deterioration of barrier and microbial product translocation. Inhibition of inflammation by general anti-inflammatory drugs or by specific inactivation of inflammatory signaling nodes (cytokines, transcription factors) decreases tumor incidence and growth in animal models and reduces the risk of cancer development and related death in humans. Unresolved questions are how TEI is induced by tumors, what are the critical mediators of TEI maintenance and its pro- tumorigenic action and how TEI acts to promote cancer and what are the time requirements for TEI action? Here we will uncover TEI mechanisms in CRC. From our previous work and preliminary data it is known that IL-23 regulates the IL-17 pathway that is essential for CRC growth. However, the identity of CRC-specific microbial stimuli, as well as the identity of myeloid cells producing IL-23 and the identity of IL-23R expressing, IL-23-responsive cells is not known. Furthermore, while it is likely that TEI promotes CRC during later stages of tumor development, it is not known whether “early” TEI induction during CRC inception is important for CRC outgrowth. Based on preliminary data we hypothesize that strongly adhesive bacteria stimulate IL-23 expression in tumor myeloid cells and IL-23 activates pro-tumorigenic IL-17 production from T cells and innate lymphoid cells (ILC) to promote CRC by acting within CRC TME, and that mechanisms operate even in early CRC. Proposed Specific Aims which are modified for the revised application are the following: (1) Define the tumor-specific microbial stimuli required to control TEI in CRC. (2) Define subsets of tumor myeloid cells required for IL-23 production and TEI induction in CRC; and 3) Examine microenvironmental mechanisms of IL-17 TEI mediated CRC and temporal requirements for TEI during CRC promotion. Overall, these studies represent a comprehensive approach integrating immunology, genetics and cancer biology to yield basic insights into the role of specific microbes in inducing TEI to promote CRC. We will methodically test various cell compartments within the TME responding to CRC-specific microbial signals, producing IL-23 and responding to IL-23; and how TEI drives CRC via its action on cells within the CRC TME. This will be a key to understand how inflammatory and cancer cells communicate within the Tumor Microenvironment and will identify targets for novel preventive/therapeutic breakthroughs. This work will establish a rationale for the specific elimination of risk-associated populations of microbes and neutralization of cytokine pathways within the CRC TME as a means of limiting CRC progression.

项目概要 肿瘤微环境（TME），特别是肿瘤浸润炎症细胞，是一个重要组成部分 的肿瘤发生。大多数实体瘤表现出一种自相矛盾的招募免疫细胞和免疫细胞的能力。 上调有助于肿瘤进展的炎症介质。我们首先将这个过程定义为“肿瘤 引发炎症”（TEI），并表明在结直肠癌（CRC）中，TEI 在早期就被诱导。 肿瘤发生，特别是由于癌基因诱导的肿瘤特异性屏障和屏障恶化 微生物产物易位。通过一般抗炎药或特定药物抑制炎症 炎症信号节点（细胞因子、转录因子）失活可降低肿瘤发生率 动物模型中的生长并降低人类患癌症和相关死亡的风险。未解决 问题是肿瘤如何诱导 TEI、TEI 维持的关键介质是什么及其亲 致瘤作用以及 TEI 如何发挥促进癌症的作用以及 TEI 作用的时间要求是什么？ 在这里，我们将揭开 CRC 中的 TEI 机制。从我们之前的工作和初步数据可知 IL-23 调节对 CRC 生长至关重要的 IL-17 途径。然而，CRC 特定的身份 微生物刺激，以及产生 IL-23 的骨髓细胞的身份和表达 IL-23R 的身份， IL-23 反应性细胞尚不清楚。此外，虽然 TEI 很可能在后期阶段促进 CRC 肿瘤发展，目前尚不清楚 CRC 起始期间“早期”TEI 诱导对于 CRC 是否重要 生长出来的。根据初步数据，我们假设强粘附细菌会刺激 IL-23 肿瘤骨髓细胞和 IL-23 中的表达激活 T 细胞和先天性细胞产生促肿瘤性 IL-17 淋巴细胞 (ILC) 通过在 CRC TME 内发挥作用来促进 CRC，并且该机制甚至在早期就起作用 CRC。针对修订后的申请进行修改的拟议具体目标如下： (1) 定义 控制 CRC 中 TEI 所需的肿瘤特异性微生物刺激。 (2)定义肿瘤骨髓细胞亚群 CRC 中 IL-23 产生和 TEI 诱导所需； 3）检查微环境机制 IL-17 TEI 介导 CRC 以及 CRC 促进期间 TEI 的时间要求。 总的来说，这些研究代表了一种整合免疫学、遗传学和癌症的综合方法 生物学，以深入了解特定微生物在诱导 TEI 促进 CRC 中的作用。我们将 有条不紊地测试 TME 内对 CRC 特异性微生物信号作出反应的各种细胞区室， 产生IL-23并对IL-23作出反应；以及 TEI 如何通过其对 CRC TME 内细胞的作用来驱动 CRC。 这将是了解炎症细胞和癌细胞如何在肿瘤内沟通的关键 微环境并将确定新的预防/治疗突破的目标。这项工作将 为具体消除与风险相关的微生物群体和中和 CRC TME 内的细胞因子途径作为限制 CRC 进展的一种手段。