Dysbiosis-induced impairment of tumoral leukocyte extravasation

微生态失调引起的肿瘤白细胞外渗损伤

• 批准号: 9150923
• 负责人: Ruud P.M. Dings
• 金额: $ 27.45万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9150923
• 关键词: Affect; Antibiotics; Bacteria; Binding; Cancer Patient; Cell Adhesion Molecules; Chronic; Clinical; Colonic Neoplasms; Cyclophosphamide; Development; Disease; Doctor of Philosophy; Dorsal; E-Selectin; Ear; Endothelial Cells; Extravasation; Flow Cytometry; Goals; Human; Image; Immune; Immunity; Immunofluorescence Immunologic; Immunologic Surveillance; Immunosuppression; Impairment; In Vitro; Inflammation; Inflammatory Response; Intercellular adhesion molecule 1; International; Intervention; Lead; Leukocytes; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Methods; Modeling; Mus; Pathogenesis; Pharmaceutical Preparations; Population; Primary Neoplasm; Production; Quality of life; Research; Research Personnel; Ribosomal RNA; Risk; Serum; Shapes; Specialist; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Immunity; Vascular Cell Adhesion Molecule-1; anticancer treatment; base; cancer therapy; cell stroma; colon carcinogenesis; cytokine; cytotoxic; gut microbiota; improved; in vivo; melanoma; metabolome; microbial; microbiota; mouse model; novel; ovarian neoplasm; response; tumor; tumor growth; tumor microenvironment; tumor progression; vascular bed

PROJECT SUMMARY/ABSTRACT Gut microbiota profoundly shapes immunity in humans. Dysbiosis, a disturbance in the quantity and composition of gut microbiota, leads to aberrant immune development and functioning and increases the risk of various diseases, including cancer. The effects of dysbiosis on non-gastrointestinal (non-GI) cancers are largely unknown. Moreover, the mechanistic effects of dysbiosis on endothelial-mediated immune surveillance in non-GI primary tumor microenvironment (TME) are unexplored. The goal of this proposal is to unravel the mechanisms by which dysbiosis impairs immune surveillance (via leukocyte extravasation and subsequent activation), specifically focusing on endothelial cell/stroma modulation. Our objective is to delineate the systemic influence of dysbiosis-generated cytokine profiles on endothelial-associated immune surveillance in non-GI TME. Based on our preliminary studies, our central hypothesis is that changes in cytokine expression during dysbiosis downregulate endothelial adhesion molecules (EAMs) such as ICAM-1, VCAM, and E- selectin. These EAMs are crucial for leukocytes to bind and adhere to tumor endothelial cells and transmigrate into the tumor, while therapeutics that upregulate EAMs improve extravasation. In particular, we will investigate the dysbiosis-induced modulation of EAMs in two primary non-GI tumors—melanoma and ovarian cancer—and the leukocyte extravasation enhancement effects by compounds that modulate EAMs. In the following Specific Aims we will test our hypothesis by measuring and analyzing: the induction of dysbiosis, changes in microbiota, non‒tumor-EAMs and tumor-EAMs, tumor growth curves, serum cytokine levels, and leukocyte extravasation in nontumor tissues and in tumors by using our established methods (e.g., 16S rRNA sequencing, real-time imaging and in vivo flow cytometry, immunofluorescence). We will associate changes in microbiota (abundance, diversity, and composition) with the downstream effects on EAMs and leukocyte extravasation in tumor-bearing and non‒tumor-bearing mice with and without cancer therapeutics. Specific Aim 1. Characterize the effects of dysbiosis on EAM expression and leukocyte-endothelial interactions in non–tumor-bearing mice. Specific Aim 2. Characterize the effects of dysbiosis on endothelial-based immune surveillance in tumors. Specific Aim 3. Enhance tumoral leukocyte extravasation by modulating EAM expression during dysbiosis. This research is significant because determining if dysbiosis contributes to tumor progression by modulating the TME will improve our understanding of microbiota and cancer crosstalk in melanoma and ovarian tumors, which could lead to novel cancer therapeutics and increase the efficacy of existing ones.

项目总结/摘要 肠道微生物群深刻地塑造了人类的免疫力。生态失调，数量和 肠道微生物群的组成，导致异常的免疫发育和功能，并增加 各种疾病，包括癌症。生态失调对非胃肠道（非GI）癌症的影响 大部分未知。此外，微生态失调对内皮介导的免疫监视的机制影响 在非GI原发性肿瘤微环境（TME）中未被探索。 这项提案的目标是解开生态失调损害免疫监视的机制 (via白细胞外渗和随后的活化），特别是集中在内皮细胞/基质 调变我们的目的是描述生态失调产生的细胞因子谱的系统性影响， 非GI TME中的内皮相关免疫监视。根据我们的初步研究， 假设是在生态失调期间细胞因子表达的变化下调了内皮粘附 在一些实施方案中，所述药物组合物包括细胞间粘附分子（EAM），如ICAM-1、VCAM和E-选择素。这些EAM对于白细胞的结合和 粘附于肿瘤内皮细胞并迁移到肿瘤中，而上调EAM的治疗剂 改善外渗。特别是，我们将研究两个环境中的生态失调诱导的EAM调制， 原发性非胃肠道肿瘤-黑色素瘤和卵巢癌-以及白细胞外渗增强效应 通过调节EAM的化合物。 在下面的具体目标中，我们将通过测量和分析来检验我们的假设： 生态失调，微生物群的变化，非肿瘤-EAM和肿瘤-EAM，肿瘤生长曲线，血清细胞因子 水平和白细胞外渗在非肿瘤组织和肿瘤中通过使用我们建立的方法（例如， 16 S rRNA测序、实时成像和体内流式细胞术、免疫荧光）。我们将联合 微生物群（丰度、多样性和组成）的变化及其对EAM的下游影响， 在有和没有癌症治疗的情况下，荷瘤和非荷瘤小鼠中的白细胞外渗。 具体目标1.表征生态失调对EAM表达和白细胞-内皮细胞 在非荷瘤小鼠中的相互作用。 具体目标2。描述生态失调对肿瘤中基于内皮的免疫监视的影响。 具体目标3。在微生态失调期间通过调节EAM表达增强肿瘤白细胞外渗。 这项研究是重要的，因为确定是否生态失调有助于肿瘤进展， 调节TME将提高我们对黑色素瘤中微生物群和癌症串扰的理解， 卵巢肿瘤，这可能导致新的癌症治疗方法，并提高现有的疗效。