Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.
Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Redox Biol. 2022 Oct;56:102463. doi: 10.1016/j.redox.2022.102463. Epub 2022 Sep 2.
Single-cell RNA-sequencing (scRNA-seq) presents better insights into cell behavior in the context of a complex tumor microenvironment by profiling single-cell populations. However, the mechanisms underlying treatment failure in hepatocellular carcinoma (HCC) are poorly understood. In this study, we performed deep scRNA-seq on immune cells under the isolation in peripheral blood, cancer tissues, and nearby common tissues of four HCC cases and two non-cancer controls, and 212,494 cells were included in the analysis. We identified distinct immune cell subtypes, enriched pathways for differential genes, and delineated associated developmentally relevant trajectories. APOC1 was found over-expressed in tumor-associated macrophages (TAMs) of HCC tissues than in normal tissues. Inhibition of APOC1 reversed the M2 phenotype to the M1 phenotype via the ferroptosis pathway in TAMs from HCC. Tumors in APOC1 C57BL/6 mice demonstrated consistent attenuation compared to wild-type (WT) mice. Mass spectrometry results revealed that the relative proportion of M2 macrophages, B cells, and CD4 T cells in the APOC1 group exhibited a downward expression compared with the WT group, whereas CD8 T cells, M1 macrophages, and NK cells exhibited an upward trend. Finally, APOC1 was found to be negatively correlated with the expression of PD1/PD-L1 in human HCC samples. In conclusion, the present study demonstrated that inhibiting APOC1 can promote the transformation of M2 macrophages into M1 macrophages via the ferroptosis pathway, thereby reshaping the tumor immune microenvironment and improving the anti-PD1 immunotherapy for HCC, providing a new strategy for improving the therapeutic effect of anti-PD1, and bringing new hope to HCC patients.
单细胞 RNA 测序（scRNA-seq）通过分析单细胞群体，更好地了解复杂肿瘤微环境中的细胞行为。然而，肝细胞癌（HCC）治疗失败的机制仍知之甚少。在这项研究中，我们对 4 例 HCC 病例和 2 例非癌对照患者外周血、肿瘤组织和附近常见组织中免疫细胞进行了深度 scRNA-seq 分析，共纳入了 212494 个细胞。我们鉴定了不同的免疫细胞亚型，富集了差异基因的通路，并描绘了相关的发育相关轨迹。APOC1 在 HCC 组织中的肿瘤相关巨噬细胞（TAMs）中表达高于正常组织。APOC1 抑制剂通过 TAMs 中的铁死亡途径将 M2 表型逆转至 M1 表型。与野生型（WT）小鼠相比，APOC1 C57BL/6 小鼠的肿瘤显示出一致的衰减。质谱结果显示，APOC1 组中 M2 巨噬细胞、B 细胞和 CD4 T 细胞的相对比例与 WT 组相比呈下降趋势，而 CD8 T 细胞、M1 巨噬细胞和 NK 细胞呈上升趋势。最后，APOC1 与人类 HCC 样本中 PD1/PD-L1 的表达呈负相关。总之，本研究表明，抑制 APOC1 可以通过铁死亡途径促进 M2 巨噬细胞向 M1 巨噬细胞的转化，从而重塑肿瘤免疫微环境，提高 HCC 的抗 PD1 免疫治疗效果，为提高抗 PD1 的治疗效果提供了新策略，为 HCC 患者带来了新的希望。
