Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Front Immunol. 2023 Feb 9;14:1033497. doi: 10.3389/fimmu.2023.1033497. eCollection 2023.
Although multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME.
In this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction.
A total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis.
Our study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.
尽管出现了多种靶向治疗方法，但肝细胞癌（HCC）仍然是癌症相关死亡的最常见原因之一。免疫抑制性肿瘤微环境（TME）是 HCC 发生和发展的关键因素。新兴的 scRNA-seq 使得高分辨率地研究 TME 成为可能。本研究旨在揭示 HCC 中免疫细胞之间的免疫代谢相互作用，并为调节免疫抑制性 TME 提供新策略。
本研究对 HCC 的配对肿瘤和肿瘤周围组织进行了 scRNA-seq。描绘了 TME 中免疫群体的组成和分化轨迹。利用 CellphoneDB 计算鉴定出的聚类之间的相互作用。此外，还进行了流式细胞术、RT-PCR 和 Seahorse 实验，以探索细胞间相互作用的潜在代谢和表观遗传机制。
共鉴定出 19 个免疫细胞簇，其中 7 个与 HCC 预后密切相关。此外，还呈现了 T 细胞的分化轨迹。此外，还鉴定出一个新的群体，即 CD3+C1q+肿瘤相关巨噬细胞（TAM），并发现其与 CD8+CCL4+T 细胞有显著相互作用。与肿瘤周围组织相比，其在肿瘤中的相互作用减弱。此外，还在败血症患者的外周血中验证了这个新发现的集群的动态存在。此外，我们发现 CD3+C1q+TAM 通过 C1q 信号诱导的代谢和表观遗传重编程影响 T 细胞免疫，从而可能影响肿瘤预后。
本研究揭示了 CD3+C1q+TAM 与 CD8+CCL4+T 细胞之间的相互作用，可能为解决 HCC 中的免疫抑制性 TME 提供启示。
