The School of Basic Medical Sciences, Fujian Medical University, No. 1, Xue Yuan Road, University Town, Fuzhou, Fujian 350122, China.
Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian 350014, China.
J Leukoc Biol. 2024 Sep 2;116(3):565-578. doi: 10.1093/jleuko/qiae159.
Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC.
虽然肿瘤细胞来源的微颗粒 (MPs) 疫苗据称可引发多种癌症的抗肿瘤免疫反应，但 Hepa1-6 细胞来源的 MPs 被树突状细胞 (DC) 摄取的机制，以及将 MPs 抗原信息传递给 CD8+T 细胞以发挥其抗肝癌 (HCC) 作用的机制仍不清楚。此外， MPs 与小分子药物 MSI-1436（蛋白酪氨酸磷酸酶 1B（PTP1B）抑制剂）联合在 HCC 中的作用尚未见报道。在这项研究中，蛋白质质谱分析联合细胞学揭示 MPs 主要通过网格蛋白介导的内吞作用和吞噬作用途径被 DC 摄取，并主要定位于溶酶体中。用 MPs 负载的 DC 刺激 CD8+T 细胞后，检测到高浓度的肿瘤坏死因子-α和干扰素-γ。此外，MPs 与 MSI-1436 联合进一步抑制了 C57BL/6 荷瘤小鼠 HCC 细胞的增殖，这与外周血、脾脏和肿瘤微环境中的 CD4+/CD8+T 细胞计数密切相关。从机制上讲， MPs 与 MSI-1436 的联合发挥了更强的抗 HCC 作用，这可能与进一步抑制 PTP1B 的表达有关。总体而言， MPs 与 MSI-1436 的联合比 MPs 或 MSI-1436 单独使用发挥更强的抗肿瘤作用。因此， MPs 与 MSI-1436 的联合可能是治疗 HCC 的一种有前途的方法。
