Surgery triggered immune response and liver metastases

项目总结 结直肠癌是全世界死亡的毁灭性原因，大多数患者死于结直肠癌。 肝转移的结果。在可行的情况下，切除肝转移瘤可改善总体和 无病生存；然而，手术切除后肝脏复发的患者中有50%-60%。 治疗失败的主要原因。术前运动疗法(Pex)，已被证明是改善的 腹部大手术的结果。众所周知，运动对外科手术有好处。 调节多种机制的结果，包括改变先天免疫的数量和功能 细胞提供抗炎环境。我们最近的发现表明，PEX显著地 减轻肝脏手术引起的肝脏炎症反应(即缺血/再灌流)。PEX诱导了一个 常驻巨噬细胞(Kupffer细胞，KCs)的抗炎表型通过以下方式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KCs中引起显著的转录变化，而且在中性粒细胞中也引起显著的转录变化 肿瘤微环境中的髓系抑制细胞(PMN-MDSCs)。此外，我们的 初步数据显示，Pex显著减少PMN-MDSC在细胞外形成中性粒细胞 陷阱(Nets)，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。 考虑到这些发现，我们假设PEX可以改善手术应激诱导的PRO-2。 致瘤性炎症反应和维持抗肿瘤免疫微环境 肝脏。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 豁免权。我们将测试Pex通过代谢诱导KCs抗肿瘤训练免疫的假设。 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 抑制PMN-MDSC形成Net重塑TME抑制肝转移瘤 成长。在目标3中，我们将验证Pex对肝手术患者TME重塑的影响。 转移性结直肠癌。我们的建议将描述PEX在调节细胞周期中的分子机制 I/R诱导的结直肠癌转移TME中的免疫细胞在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，在 改善癌症患者的手术结果。

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.