Surgery triggered immune response and liver metastases

项目摘要 结直肠癌是世界范围内死亡率的毁灭性原因，大多数患者死亡的原因是因为癌症。 肝转移的结果。在可行的情况下，切除肝转移瘤可改善总体和 无病生存;然而，手术切除后的肝复发发生在50-60%的患者中， 治疗失败的主要原因。术前运动疗法（PEx），已被证明可以改善 腹部大手术的结果。众所周知，锻炼对外科手术有有益的影响。 结果通过调节多种机制，包括先天免疫的数量和功能的改变， 细胞来提供抗炎环境。我们最近的研究结果表明，PEx显着 减弱肝脏手术诱导的肝脏炎症反应（即，缺血/再灌注）。PEx诱导 驻留巨噬细胞（枯否细胞，KC）中的抗炎表型，通过以下方式引起不同的代谢变化： 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著的转录组学变化， 骨髓源性抑制细胞（PMN-MDSC）在肿瘤微环境（TME）。而且我们的 初步数据表明，PEx显著降低PMN-MDSC形成中性粒细胞外 陷阱（NET），这是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改善了手术应激诱导的促凋亡， 致瘤性炎症反应，并维持抗肿瘤免疫微环境， 肝脏在目的1中，我们将描述PEx如何诱导KC介导的抗肿瘤训练的机制。 免疫力我们将检验以下假设：PEx通过代谢途径在KC中诱导抗肿瘤训练免疫力。 表观遗传重编程，特别是衣康酸/IRG 1途径。在目标2中，我们将确定PEx 通过抑制NETs的PMN-MDSC形成来重塑TME以抑制肝转移性肿瘤 增长在目标3中，我们将验证PEx对接受肝脏手术的患者TME重塑的影响， 窝藏egdr突变我们的建议将描绘PEx在调节的分子机制， 免疫细胞在I/R诱导的结直肠转移的TME中的作用。这些研究中发现的机制 将为设计新的运动疗法提供基础，这些疗法以机制为基础， 改善癌症患者的手术效果。

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.