Ye Guiqin, Sun Xin, Li Jiuzhou, Pu Maomao, Zhang Jianbin
Clinical Laboratory, The Yuhuan People's Hospital, Taizhou 317600, China; Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
J Adv Res. 2025 Jan 2. doi: 10.1016/j.jare.2024.12.045.
Parkin-mediated mitophagy is essential for clearing damaged mitochondria, and it inhibits tumour development. The role of mitophagy in modulating tumour immunity is becoming clearer, but the underlying mechanism is still poorly understood.
This study was designed to examine the role of Parkin in the immune microenvironment of liver tumours induced by carbon tetrachloride (CCl).
Single-cell RNA sequencing analysis, Western blot, immunofluorescence and co-immunoprecipitation were used to verify the mechanism of Parkin affecting the tumour microenvironment by altering the expression of PD-1.
Our data revealed that Park2 mice showed severe liver damage and increased malignancy. Single-cell RNA sequencing analysis of T lymphocytes in liver tumours showed that the number of cytotoxic CD8 T cells (Gzmb/Ifng/Fasl) was significantly decreased and the number of exhausted CD8 T cells (Pdcd1/Lag3/Tigit/Havcr2/Ctla4) was significantly increased in Park2 mice, indicating the immune suppressive microenvironment. Single-cell RNA sequencing analysis of myeloid-derived cells also displayed the increase of M2-like macrophages in Park2 mice. Through quantitative proteomic analysis, it was found that the differential protein expression between the two groups mainly localized in the plasma membrane and extracellular, including PD-1, MHC-Ⅰ molecules etc., and was mainly associated with PD-1 and antigen presentation pathways. It could impair the antitumour immune response with Parkin deficiency. Parkin deficiency leads to the decrease of hepatic mitophagy levels and the formation of an immune suppressive microenvironment, which promotes the tumourigenesis of liver cancer.
As an E3 ubiquitin ligase, Parkin induces the ubiquitination and degradation of PD-1 in liver cancer and could influence antitumour immunity through the PD-1/PD-L1 signalling pathway. Thus, remodeling the tumour microenvironment through the reintroduction of Parkin or enhancement of mitophagy could activate the anti-tumour immune response and improve the immunotherapy efficacy, which may be a promising strategy for the treatment of HCC.
帕金蛋白介导的线粒体自噬对于清除受损线粒体至关重要，并且它能抑制肿瘤发展。线粒体自噬在调节肿瘤免疫中的作用正变得越来越清晰，但其潜在机制仍知之甚少。
本研究旨在探讨帕金蛋白在四氯化碳（CCl）诱导的肝肿瘤免疫微环境中的作用。
采用单细胞RNA测序分析、蛋白质免疫印迹、免疫荧光和免疫共沉淀等方法，验证帕金蛋白通过改变程序性死亡受体1（PD-1）的表达来影响肿瘤微环境的机制。
我们的数据显示，Park2小鼠表现出严重的肝损伤和恶性程度增加。对肝肿瘤中T淋巴细胞进行单细胞RNA测序分析表明，Park2小鼠中细胞毒性CD8 T细胞（颗粒酶B/干扰素γ/ Fas配体）的数量显著减少，而耗竭性CD T细胞（程序性死亡受体1/淋巴细胞活化基因3/ T细胞免疫球蛋白和粘蛋白结构域分子3/甲型肝炎病毒细胞受体2/细胞毒性T淋巴细胞相关蛋白4）的数量显著增加，表明存在免疫抑制微环境。对髓系来源细胞进行单细胞RNA测序分析也显示Park2小鼠中M2样巨噬细胞增加。通过定量蛋白质组学分析发现，两组之间的差异蛋白表达主要定位于质膜和细胞外，包括PD-1、主要组织相容性复合体Ⅰ类分子等，并且主要与PD-1和抗原呈递途径相关。帕金蛋白缺乏会损害抗肿瘤免疫反应。帕金蛋白缺乏导致肝脏线粒体自噬水平降低并形成免疫抑制微环境，从而促进肝癌的发生。
作为一种E3泛素连接酶，帕金蛋白可诱导肝癌中PD-1的泛素化和降解，并可能通过PD-1/程序性死亡受体配体1信号通路影响抗肿瘤免疫。因此，通过重新引入帕金蛋白或增强线粒体自噬来重塑肿瘤微环境，可以激活抗肿瘤免疫反应并提高免疫治疗效果，这可能是治疗肝癌的一种有前景的策略。
