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ACSL6 激活的 IL-18R1-NF-κB 促进了 IL-18 介导的肿瘤免疫逃逸和肿瘤进展。

ACSL6-activated IL-18R1-NF-κB promotes IL-18-mediated tumor immune evasion and tumor progression.

机构信息

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai, Guangdong 519000, China.

出版信息

Sci Adv. 2024 Sep 20;10(38):eadp0719. doi: 10.1126/sciadv.adp0719. Epub 2024 Sep 18.

DOI:10.1126/sciadv.adp0719
PMID:39292786
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11409972/
Abstract

Aberrant activation of IL-18 signaling regulates tumor immune evasion and progression. However, the underlying mechanism remains unclear. Here, we report that long-chain acyl-CoA synthase 6 (ACSL6) is highly expressed in liver cancer and correlated with poor prognosis. ACSL6 promotes tumor growth, metastasis, and immune evasion mediated by IL-18, independent of its metabolic enzyme activity. Mechanistically, upon IL-18 stimulation, ACSL6 is phosphorylated by ERK2 at S674 and recruits IL-18RAP to interact with IL-18R1, thereby reinforcing the IL-18R1-IL-18RAP heterodimer and triggering NF-κB-dependent gene expression to facilitate tumor development. Furthermore, the up-regulation of CXCL1 and CXCL5 by ACSL6 promotes tumor-associated neutrophil and tumor-associated macrophage recruitment, thereby inhibiting cytotoxic CD8 T cell infiltration. Ablation or S674A mutation of ACSL6 potentiated anti-PD-1 therapeutic efficacy by increasing the effector activity of intertumoral CD8 T cells. We revealed that ACSL6 is a potential adaptor that activates IL-18-NF-κB axis-mediated tumor immune evasion and provides valuable insights for developing effective immunotherapy strategies for cancer.

摘要

IL-18 信号的异常激活调节肿瘤免疫逃逸和进展。然而，其潜在机制尚不清楚。在这里，我们报告长链酰基辅酶 A 合成酶 6（ACSL6）在肝癌中高度表达，并与预后不良相关。ACSL6 独立于其代谢酶活性，促进肿瘤生长、转移和 IL-18 介导的免疫逃逸。在机制上，ACSL6 在受到 IL-18 刺激后，ERK2 在 S674 处磷酸化 ACSL6，并募集 IL-18RAP 与 IL-18R1 相互作用，从而增强 IL-18R1-IL-18RAP 异二聚体，并触发 NF-κB 依赖性基因表达，促进肿瘤发展。此外，ACSL6 上调的 CXCL1 和 CXCL5 促进肿瘤相关中性粒细胞和肿瘤相关巨噬细胞的募集，从而抑制细胞毒性 CD8 T 细胞的浸润。通过增加肿瘤间 CD8 T 细胞的效应活性，ACSL6 的缺失或 S674A 突变增强了抗 PD-1 治疗的疗效。我们揭示了 ACSL6 是一种潜在的衔接蛋白，它激活了 IL-18-NF-κB 轴介导的肿瘤免疫逃逸，并为开发有效的癌症免疫治疗策略提供了有价值的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9563/11409972/599cbefe7019/sciadv.adp0719-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9563/11409972/599cbefe7019/sciadv.adp0719-f8.jpg
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