State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Adv Sci (Weinh). 2023 Jun;10(16):e2207074. doi: 10.1002/advs.202207074. Epub 2023 Apr 4.
Kynurenine derivative 3-hydroxyanthranilic acid (3-HAA) is known to regulate the immune system and exhibit anti-inflammatory activity by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, the definite role of 3-HAA in the immunomodulation of hepatocellular carcinoma (HCC) is largely unexplored. An orthotopic HCC model and treated with 3-HAA by intraperitoneal injection is developed. Furthermore, cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) analyses are carried out to define the immune landscape of HCC. It is found that 3-HAA treatment can significantly suppress tumor growth in the HCC model and alter the level of various cytokines in plasma. CyTOF data shows that 3-HAA significantly increases the percentage of F4/80 CX3CR1 Ki67 MHCII macrophages and decreases the percentage of F4/80 CD64 PD-L1 macrophages. scRNA-seq analyses demonstrate that 3-HAA treatment is proved to regulate the function of M1 macrophages, M2 macrophages, and proliferating macrophages. Notably, 3-HAA inhibits the proinflammatory factors TNF and IL-6 in multiple cell subsets, including resident macrophages, proliferating macrophages, and pDCs. This study reveals the landscape of immune cell subsets in HCC in response to 3-HAA, indicating that 3-HAA may be a promising therapeutic target for HCC.
犬尿氨酸衍生物 3-羟基犬尿氨酸（3-HAA）通过抑制 T 细胞细胞因子分泌和影响巨噬细胞活性来调节免疫系统并发挥抗炎活性。然而，3-HAA 在肝细胞癌（HCC）免疫调节中的明确作用在很大程度上尚未得到探索。建立了一个原位 HCC 模型，并通过腹腔注射 3-HAA 进行治疗。此外，进行了飞行时间细胞术（CyTOF）和单细胞 RNA 测序（scRNA-seq）分析，以定义 HCC 的免疫景观。结果发现，3-HAA 处理可显著抑制 HCC 模型中的肿瘤生长，并改变血浆中各种细胞因子的水平。CyTOF 数据显示，3-HAA 显著增加了 F4/80 CX3CR1 Ki67 MHCII 巨噬细胞的百分比，并降低了 F4/80 CD64 PD-L1 巨噬细胞的百分比。scRNA-seq 分析表明，3-HAA 处理被证明可调节 M1 巨噬细胞、M2 巨噬细胞和增殖巨噬细胞的功能。值得注意的是，3-HAA 抑制了驻留巨噬细胞、增殖巨噬细胞和 pDC 等多个细胞亚群中的促炎因子 TNF 和 IL-6。本研究揭示了 HCC 中免疫细胞亚群对 3-HAA 反应的景观，表明 3-HAA 可能是 HCC 的一种有前途的治疗靶点。
