Yehezkel Adi S, Yehezkel Eyal, Abudi Nathalie, Abramovitch Rinat
The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center and faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; The Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center, Ein Karem, 91120, Jerusalem, Israel.
The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center and faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Neoplasia. 2025 Aug 28;69:101222. doi: 10.1016/j.neo.2025.101222.
BACKGROUND & AIMS: The liver is the most common site for distant metastasis. Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide and significantly increases the risk of liver metastasis in colorectal cancer (CRC) patients. We aimed to elucidate hepatic immune cells alterations in response to the metabolic stress in MAFLD and their influence on the early stages of CRC liver metastasis (CRLM).
High-fat diet (HFD) and Western diet (WD), were used to create MAFLD and MASH respectively. MC38 cancer cells were injected intrasplenically to create CRLM model. Single-cell RNA sequencing (scRNA-seq), RT-PCR and immunohistology were used to study hepatic immune-cell composition, phenotypes, and localization.
Both diets significantly increased CRLM establishment, while only WD altered hepatic inflammation. The WD-promotes IL-10 and TGF-β1 elevation, an anti-inflammatory cytokines, inhibiting cytotoxic CD8 T cells and NK cells and supporting an immunosuppressive environment. Although MASH led to an increased presence of hepatic CD8 and NK cells, their infiltration into metastatic foci was reduced and was associated with a decrease in expression of cytotoxic markers. In our murine model of MASH, CD8 T-cell depletion reduced the number of CRLM foci, which was accompanied by a decrease in IFN-γ-associated cytokines and a significant increase in the infiltration of granzyme-B expressing NK cells, ultimately enhancing cytotoxic killing ability.
This research underscores the crucial influence of diet-induced immune changes on CRLM establishment and progression. It illustrates that the co-localization of immune cells within liver metastases significantly affects their functionality, highlighting potential therapeutic strategies to balance immune exhaustion and activation.
肝脏是远处转移最常见的部位。代谢功能障碍相关脂肪性肝病（MAFLD）是全球最常见的肝脏疾病，显著增加了结直肠癌（CRC）患者肝转移的风险。我们旨在阐明MAFLD中肝脏免疫细胞对代谢应激的反应变化及其对CRC肝转移（CRLM）早期阶段的影响。
分别采用高脂饮食（HFD）和西方饮食（WD）构建MAFLD和MASH模型。通过脾内注射MC38癌细胞构建CRLM模型。采用单细胞RNA测序（scRNA-seq）、逆转录聚合酶链反应（RT-PCR）和免疫组织学方法研究肝脏免疫细胞的组成、表型和定位。
两种饮食均显著增加CRLM的形成，而只有WD改变了肝脏炎症。WD促进抗炎细胞因子白细胞介素-10（IL-10）和转化生长因子-β1（TGF-β1）升高，抑制细胞毒性CD8 T细胞和自然杀伤（NK）细胞，并支持免疫抑制环境。虽然MASH导致肝脏CD8和NK细胞数量增加，但其向转移灶的浸润减少，且与细胞毒性标志物表达降低有关。在我们的MASH小鼠模型中，CD8 T细胞耗竭减少了CRLM灶的数量，同时伴有干扰素-γ（IFN-γ）相关细胞因子减少，以及表达颗粒酶B的NK细胞浸润显著增加，最终增强了细胞毒性杀伤能力。
本研究强调了饮食诱导的免疫变化对CRLM形成和进展的关键影响。它表明肝转移灶内免疫细胞的共定位显著影响其功能，突出了平衡免疫耗竭和激活的潜在治疗策略。
Zotero 插件
