PO.IM01.02 · 免疫学
解析脂质相关巨噬细胞在肝细胞癌免疫治疗耐药中的功能
Deciphering the function of lipid-associated macrophages in immunotherapy resistance of hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。虽然免疫检查点阻断（ICB）已变革了肿瘤学，但其在HCC中的疗效受限于免疫抑制性肿瘤微环境（TME）和多样的疾病病因，缓解率低于30%。我们此前的工作确定了在临床前模型中构成ICB耐药基础的免疫排斥和髓系介导免疫抑制的几个关键转录和表观遗传驱动因素（Gut 2018、2020、2023，Sci Transl Med 2021）。为开发精准免疫疗法，识别ICB耐药患者TME内的核心调控节点至关重要。
方法：我们应用单细胞RNA测序（scRNA-seq）、单细胞转座酶可及染色质测序（scATAC-seq）和空间转录组学，研究对ICB耐药的HCC患者（来自试验NCT05873244）的TME，并以未经治疗的患者作为对照。
结果：多组学分析揭示了一个以脂质相关基因高表达为特征的肿瘤相关巨噬细胞（TAM）亚群。对开放染色质区域的生物信息学分析确定了一种转录因子（MTF），其在ICB耐药HCC的TAM中显著上调，而在未经治疗的肿瘤中则不然。空间转录组分析和多重免疫组化证实了MTF与患者肿瘤中脂质相关巨噬细胞（LAM）的共定位。在THP-1细胞中的染色质免疫沉淀测序显示，MTF结合富集于吞噬相关基因。在巨噬细胞系中的功能研究表明，敲低或过表达MTF可调节吞噬能力。整合RNA测序和Cut&Tag分析进一步阐明了其下游靶点及其在吞噬通路中的参与。
结论：本研究确定了一种新的关键转录调控因子，并提供了其在HCC ICB耐药中调节巨噬细胞吞噬作用和脂质代谢作用的机制证据。我们的发现揭示了免疫抑制性髓系图景中关键的表观遗传和转录改变，并突出了克服ICB耐药的有前景的治疗靶点。这些见解为将靶向免疫代谢轴作为对抗HCC中ICB耐药的新策略奠定了基础。
致谢：本研究由普通研究基金（14120621、14119023和14112525）、香港中文大学研究委员会直接资助（504643107）以及李嘉诚基金会资助。
查看英文原文 English abstract
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally. While immune-checkpoint blockade (ICB) has transformed oncology, its efficacy in HCC is limited by an immunosuppressive tumor microenvironment (TME) and diverse disease etiologies, yielding response rates below 30%. Our prior work identified several key transcriptional and epigenetic drivers of immune exclusion and myeloid-mediated immunosuppression underlying ICB resistance in preclinical models ( Gut 2018, 2020, 2023, Sci Transl Med 2021). To develop precise immunotherapies, it is critical to identify the central regulatory nodes within the TME of ICB-resistant patients.
Methods: We applied single-cell RNA sequencing (scRNA-seq), single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq), and spatial transcriptomics to investigate the TME of HCC patients resistant to ICBs (from trial NCT05873244), with treatment-naïve patients serving as controls.
Results: Multi-omics analysis uncovered a subcluster of tumor-associated macrophages (TAMs) characterized by high levels of lipid-associated genes. Bioinformatics analysis of open chromatin regions identified a transcription factor (MTF) that was significantly up-regulated in TAMs from ICB-resistant HCCs but not in treatment-naïve tumors. Spatial transcriptomic profiling and multiplex immunohistochemistry confirmed the co-localization of MTF with the lipid-associated macrophages (LAMs) in patient tumors. Chromatin immunoprecipitation-sequencing in THP-1 cells revealed that MTF binding was enriched in phagocytosis-related genes. Functional studies in macrophage cell lines demonstrated that knockdown or overexpression of MTF modulated phagocytic capacity. Integrated RNA sequencing and Cut&Tag analysis further delineated its downstream targets and involvement in phagocytic pathways.
Conclusions: This study identifies a novel key transcriptional regulator and provides mechanistic evidence for its role in modulating macrophage phagocytosis and lipid metabolism in HCC ICB resistance. Our findings uncover critical epigenetic and transcriptional alterations within the immunosuppressive myeloid landscape and highlight promising therapeutic targets to overcome ICB resistance. These insights lay the groundwork for targeting the immunometabolic axis as a new strategy to counteract ICB resistance in HCC.
Acknowledgment: This study is supported by the General Research Fund (14120621, 14119023 and 14112525) CUHK Research Committee-Direct Grants (504643107) and the Li Ka Shing Foundation.
利益披露 Disclosure
X. Long, None..
Y. Wang, None..
S. Huang, None..
J. Vong, None..
J. Sung, None..
L. Chan, None..
A. Cheng, None.