Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hepatol Int. 2024 Apr;18(2):582-594. doi: 10.1007/s12072-023-10595-w. Epub 2023 Oct 12.
T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects.
Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model.
Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo.
Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.
T 细胞是癌症中抗肿瘤免疫的主要效应细胞。最近的研究表明，肿瘤微环境施加的改变的脂质代谢限制了抗肿瘤免疫。然而，抑制 T 细胞控制肿瘤进展能力的肿瘤相关脂质种类变化尚不完全清楚。在这里，我们计划阐明乙型肝炎病毒（HBV）相关肝细胞癌（HCC）中明显改变的脂质成分对 T 细胞功能的影响，旨在寻找改善 T 细胞抗肿瘤作用的脂质代谢靶点。
收集 HCC 患者的肿瘤组织和非肿瘤肝脏进行 RNA 测序、脂质谱分析和 T 细胞特征分析，并进行相关性分析。此外，通过体外细胞实验和/或体内肿瘤接种模型测试显着改变的脂质成分对 T 细胞抗肿瘤潜力的影响。
HBV 相关 HCC 中改变的脂质代谢与 T 细胞反应受损同时发生。在肿瘤组织中发现了特征性脂质组成，其特征是长链酰基辅酶 A（LCAC）的积累和溶血磷脂酰胆碱（LPC）的减少。值得注意的是，积累的 LCAC 与 T 细胞耗竭和功能缺陷有关，而 LPC 与 T 细胞的抗肿瘤作用相关。特别是，LPC（20:0）和 LPC（22:0）等 LPC 的补充可直接促进 T 细胞在体外的激活和 IFN-γ分泌，并抑制体内肿瘤生长。
我们的研究强调了与 HCC 中 T 细胞失调密切相关的明显改变的脂质成分，并提出了通过减少 LCAC 和增加 LPC 来进行抗肿瘤免疫治疗的有前途的策略。
