Surgery triggered immune response and liver metastases

手术引发免疫反应和肝转移

• 批准号: 10522248
• 负责人: Hai Huang
• 金额: $ 43.26万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522248
• 关键词: Abdomen; Adoptive Transfer; Anti-Inflammatory Agents; Attenuated; Biological; Cancer Patient; Cells; Clinical; Colorectal; Colorectal Cancer; Curative Surgery; Cytometry; Data; Disease; Disease-Free Survival; Environment; Epigenetic Process; Excision; Exercise; Exercise Therapy; Foundations; Gene Expression Profile; Genetic; Goals; Growth; Hepatic; Immune; Immune response; Immunity; Immunologics; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knowledge; Kupffer Cells; Link; Liver; Macrophage; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metastasis Induction; Metastatic Neoplasm to the Liver; Micrometastasis; Modality; Modeling; Molecular; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Perioperative; Pharmacologic Substance; Phenotype; Play; Process; Proliferating; Quantitative Evaluations; Recurrence; Recurrent disease; Recurrent tumor; Relapse; Reperfusion Therapy; Resected; Risk; Role; Stains; Stress; Surgical Models; Technology; Testing; Time; Training; Treatment Failure; colon cancer patients; colorectal cancer metastasis; extracellular; immunoregulation; improved; improved outcome; infancy; inflammatory milieu; innate immune function; metastatic colorectal; mortality; mouse model; neoplastic cell; neutrophil; novel; participant enrollment; pharmacologic; predicting response; prevent; randomized, clinical trials; relapse prediction; response; single cell technology; single-cell RNA sequencing; surgery outcome; targeted treatment; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY Colorectal cancer is a devastating cause of mortality worldwide, with the majority of patients dying as a result of hepatic metastasis. When feasible, resection of hepatic metastases provides improved overall and disease-free survival; however, hepatic recurrence after surgical resection occurs in 50-60% of patients and is the major cause of treatment failure. Pre-operative exercise therapy (PEx), which has been shown to improve outcomes from major abdominal surgeries. It is known that exercise confers beneficial effects on the surgical outcome by regulating multiple mechanisms, including alteration of quantity and function of innate immune cells to provide an anti-inflammatory environment. Our recent findings demonstrate that PEx significantly attenuates liver surgery-induced hepatic inflammatory response (i.e., ischemia/reperfusion). PEx induces an anti-inflammatory phenotype in resident macrophages (Kupffer cells, KCs) causing distinct metabolic shifts by itaconate-mediated metabolic reprogramming. Our preliminary single-cell RNA-sequencing (scRNA-seq) data reveal that PEx causes dramatic transcriptomic changes not only in KCs but also in polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs) in the tumor microenvironment (TME). Furthermore, our preliminary data indicate that PEx significantly decreases PMN-MDSC from forming neutrophil extracellular traps (NETs), an important mechanism that links inflammation to nearly every stage in tumor progression. Given these findings, we hypothesize that that PEx ameliorates surgical stress-induced pro- tumorigenic inflammatory responses and sustains an anti-tumor immune microenvironment in the liver. In Aim 1, we will delineate the mechanisms of how PEx induces KC-mediated anti-tumor trained immunity. We will test the hypothesis that PEx induces an anti-tumor trained immunity in KCs via metabolic- epigenetic reprogramming, especially the itaconate/IRG1 pathway. In Aim 2, we will determine how PEx remodels the TME by suppressing PMN-MDSC formation of NETs to suppress hepatic metastatic tumor growth. In Aim 3, we will validate the effects of PEx on TME remodeling in patients undergoing liver surgery for metastatic colorectal cancer. Our proposal will delineate the molecular mechanisms of PEx in the regulation of immune cells in the TME of I/R-induced colorectal metastasis. The mechanisms discovered in these studies will provide the foundation for devising new exercise therapies that are mechanism-based and effective in improving surgical outcomes of cancer patients.

项目概要 结直肠癌是世界范围内毁灭性的死亡原因，大多数患者死于结直肠癌 肝转移的结果。在可行的情况下，切除肝转移瘤可以改善整体和 无病生存；然而，50-60%的患者在手术切除后会出现肝脏复发，并且 治疗失败的主要原因。术前运动疗法（PEx）已被证明可以改善 主要腹部手术的结果。众所周知，运动对手术有积极的影响。 通过调节多种机制来产生结果，包括改变先天免疫的数量和功能 细胞提供抗炎环境。我们最近的研究结果表明，PEx 显着 减轻肝脏手术引起的肝脏炎症反应（即缺血/再灌注）。 PEx 会诱导 常驻巨噬细胞（库普弗细胞，KC）的抗炎表型引起明显的代谢变化 衣康酸介导的代谢重编程。我们的初步单细胞 RNA 测序 (scRNA-seq) 数据 揭示 PEx 不仅在 KC 中而且在多形核中引起显着的转录组变化 肿瘤微环境（TME）中的骨髓源性抑制细胞（PMN-MDSC）。此外，我们的 初步数据表明，PEx 显着减少 PMN-MDSC 形成中性粒细胞胞外 陷阱（NET），一种将炎症与肿瘤进展的几乎每个阶段联系起来的重要机制。 鉴于这些发现，我们假设 PEx 可以改善手术应激引起的亲 致瘤性炎症反应并维持抗肿瘤免疫微环境 肝。在目标 1 中，我们将描述 PEx 如何诱导 KC 介导的抗肿瘤训练的机制 免疫。我们将测试以下假设：PEx 通过代谢在 KC 中诱导抗肿瘤训练免疫力 表观遗传重编程，尤其是衣康酸/IRG1 途径。在目标 2 中，我们将确定 PEx 如何 通过抑制 PMN-MDSC 形成 NET 来重塑 TME，从而抑制肝转移肿瘤 生长。在目标 3 中，我们将验证 PEx 对接受肝脏手术的患者 TME 重塑的影响 转移性结直肠癌。我们的提案将描述 PEx 在调节中的分子机制 I/R 诱导的结直肠转移的 TME 中的免疫细胞。这些研究中发现的机制 将为设计基于机制且有效的新运动疗法奠定基础 改善癌症患者的手术结果。