一类新型肿瘤相关巨噬细胞亚群及其代谢重编程在肝癌进展中的作用和机制研究

Tumor-associated macrophage (TAM) has a dual-role in the progression of hepatocellular carcinoma (HCC). Traditional understanding is that pro-inflammatory M1-type TAM inhibits tumor progression while anti-inflammatory M2-type TAM promotes tumor progression. The applicant previously revealed a subtype of pro-inflammatory M2-type (CD206+IL-1β+) TAM, and proved that IL-1β induces HCC cells undergo epithelial-to-mesenchymal transition and HCC progression. However, it is unknown how the pro-inflammatory function of this TAM subtype is regulated. Our preliminary findings showed that free fatty acid level was increased in HCC microenvironment, and that fatty acid oxidation facilitated IL-1β secretion of HCC-related M2-type TAMs. Succinate dehydrogenase (SDH) was found to be critical in this process. We thus hypothesize that the increased fatty acid in HCC microenvironment can promote fatty acid oxidation and enhance SDH activity by a metabolic reprogramming manner in CD206+IL-1β+ TAMs, leading to IL-1β secretion and HCC progression. In this study, we will use materials including but not limited to human tissue, induced pluripotent cells, and genetic engineering mouse models to confirm the effects of metabolically reprogrammed TAMs by HCC cells through a "tumor cell-microenvironment-TAM" view. In addition, we hope to uncover the molecular mechanisms by which fatty acid oxidation regulates IL-1β secretion of TAMs from an SDH view. Our project will explore the way of HCC educate TAM from a novel perspective, which can contribute to deeper understanding of the "tumor-inflammation" theory and may be helpful for the development of novel strategies for HCC treatment.

肿瘤相关巨噬细胞（TAM）在肝癌进展中具有双重作用--促炎的M1型TAM抑制肿瘤而抑炎的M2型TAM促进肿瘤。申请人曾首次报道肝癌中存在促炎的M2型（CD206+IL-1β+）TAM，且IL-1β促进肝癌上皮间质转化和转移。但该群TAM在肝癌中发挥促炎功能的调控机制尚不清楚。初步研究发现肝癌微环境中脂肪酸增多，脂肪酸氧化促进M2型TAM分泌IL-1β，且琥珀酸脱氢酶（SDH）发挥关键作用。我们据此猜测：HCC中高脂肪酸微环境促进CD206+IL-1β+ TAM脂肪酸氧化，通过代谢重编程增加SDH活性，促进IL-1β分泌和肝癌进展。本课题拟从"癌细胞-微环境-TAM"角度明确癌细胞对TAM的代谢调控作用，从SDH活性角度阐明脂肪酸氧化调节TAM IL-1β分泌的分子机制。本研究将从代谢调控这一全新角度探讨肝癌"驯化"TAM促癌机制，丰富"炎-癌"理论，有助于开发肝癌治疗新方法。

项目背景：肿瘤相关巨噬细胞(TAM)炎症反应在促进肝细胞肝癌(HCC)进展中具有重要作用，以IL -1β为代表的炎症反应可促进HCC转移。但作为HCC中主要类群的M2型TAM的促炎机制尚不清楚。前期研究发现肝癌微坏死与微环境中促炎巨噬细胞相关。.主要研究内容：肝癌微坏死的临床价值和生物学意义；由肝癌微坏死所诱导的IL-1β+CD206+巨噬细胞的表面生物标志物、诱导活化机制、代谢特征、促癌作用和分子机制；肝癌细胞与微环境中巨噬细胞通过细胞代谢实现“对话”的分子机制。..重要结果：发现了一个新的巨噬细胞亚群和一类新的TLR-4配体，揭示了其表面生物标志物、诱导活化机制、代谢特征、促癌作用和分子机制；发现微坏死是肝癌恶性生物学行为的生物标志物；提出肝癌治疗新靶点CD61；根据局部免疫特性提出了一种肝癌新分型——免疫正常型、免疫荒漠型、免疫抑制型；制定了根据CD45和Foxp3的便捷有效的分型指标和免疫组化方法；阐明了不同免疫分型背后的代谢调控机制。..科学意义：丰富了巨噬细胞的分类体系，加深了对TLR-4受体活化方式的理解；针对临床肝癌患者，利用微坏死评分能够筛选出从辅助治疗获益的患者，对肝切除术和肝移植手术治疗肝癌的适应证人群实现了优化，有望实现肝癌精准治疗。