School of Food Science and Engineering, South China University of Technology, Guangzhou, 510641, Guangdong, People's Republic of China.
State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, People's Republic of China.
Cancer Immunol Immunother. 2024 May 14;73(7):128. doi: 10.1007/s00262-024-03694-6.
The majority of the immune cell population in the tumor microenvironment (TME) consists of tumor-associated macrophages (TAM), which are the main players in coordinating tumor-associated inflammation. TAM has a high plasticity and is divided into two main phenotypes, pro-inflammatory M1 type and anti-inflammatory M2 type, with tumor-suppressive and tumor-promoting functions, respectively. Considering the beneficial effects of M1 macrophages for anti-tumor and the high plasticity of macrophages, the conversion of M2 TAM to M1 TAM is feasible and positive for tumor treatment. This study sought to evaluate whether the glycopeptide derived from simulated digested Codonopsis pilosula extracts could regulate the polarization of M2-like TAM toward the M1 phenotype and the potential regulatory mechanisms. The results showed that after glycopeptide dCP1 treatment, the mRNA relative expression levels of some M2 phenotype marker genes in M2-like TAM in simulated TME were reduced, and the relative expression levels of M1 phenotype marker genes and inflammatory factor genes were increased. Analysis of RNA-Seq of M2-like TAM after glycopeptide dCP1 intervention showed that the gene sets such as glycolysis, which is associated with macrophage polarization in the M1 phenotype, were significantly up-regulated, whereas those of gene sets such as IL-6-JAK-STAT3 pathway, which is associated with polarization in the M2 phenotype, were significantly down-regulated. Moreover, PCA analysis and Pearson's correlation also indicated that M2-like TAM polarized toward the M1 phenotype at the transcriptional level after treatment with the glycopeptide dCP1. Lipid metabolomics was used to further explore the efficacy of the glycopeptide dCP1 in regulating the polarization of M2-like TAM to the M1 phenotype. It was found that the lipid metabolite profiles in dCP1-treated M2-like TAM showed M1 phenotype macrophage lipid metabolism profiles compared with blank M2-like TAM. Analysis of the key differential lipid metabolites revealed that the interconversion between phosphatidylcholine (PC) and diacylglycerol (DG) metabolites may be the central reaction of the glycopeptide dCP1 in regulating the conversion of M2-like TAM to the M1 phenotype. The above results suggest that the glycopeptide dCP1 has the efficacy to regulate the polarization of M2-like TAM to M1 phenotype in simulated TME.
肿瘤微环境（TME）中的大多数免疫细胞群体由肿瘤相关巨噬细胞（TAM）组成，它们是协调肿瘤相关炎症的主要参与者。TAM 具有高度的可塑性，分为两种主要表型，促炎 M1 型和抗炎 M2 型，分别具有肿瘤抑制和促进肿瘤的功能。鉴于 M1 巨噬细胞对抗肿瘤的有益作用和巨噬细胞的高可塑性，将 M2 TAM 转化为 M1 TAM 是可行的，对肿瘤治疗有积极作用。本研究旨在评估从模拟消化党参提取物中获得的糖肽是否可以调节模拟 TME 中的 M2 样 TAM 向 M1 表型的极化，并探讨其潜在的调控机制。结果表明，糖肽 dCP1 处理后，模拟 TME 中 M2 样 TAM 中一些 M2 表型标志物基因的 mRNA 相对表达水平降低，而 M1 表型标志物基因和炎症因子基因的相对表达水平升高。糖肽 dCP1 干预后 M2 样 TAM 的 RNA-Seq 分析表明，与 M1 表型中巨噬细胞极化相关的糖酵解等基因集显著上调，而与 M2 表型中极化相关的基因集如 IL-6-JAK-STAT3 通路等显著下调。此外，PCA 分析和 Pearson 相关性也表明，糖肽 dCP1 处理后 M2 样 TAM 在转录水平上向 M1 表型极化。进一步采用脂质组学探索糖肽 dCP1 调节 M2 样 TAM 向 M1 表型极化的疗效。结果发现，与空白 M2 样 TAM 相比，dCP1 处理后的 M2 样 TAM 的脂质代谢物谱呈现 M1 表型巨噬细胞脂质代谢谱。对关键差异脂质代谢物的分析表明，磷酸胆碱（PC）和二酰基甘油（DG）代谢物之间的相互转化可能是糖肽 dCP1 调节 M2 样 TAM 向 M1 表型转化的中心反应。上述结果表明，糖肽 dCP1 具有在模拟 TME 中调节 M2 样 TAM 向 M1 表型极化的功效。
