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来自癌症相关成纤维细胞的细胞外囊泡包裹的长链非编码 RNA 通过下调胰腺癌中的 HLA-A 促进免疫逃逸。

Extracellular vesicle-packaged lncRNA from cancer-associated fibroblasts promotes immune evasion by downregulating HLA-A in pancreatic cancer.

机构信息

Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.

Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

出版信息

J Extracell Vesicles. 2024 Jul;13(7):e12484. doi: 10.1002/jev2.12484.

DOI:10.1002/jev2.12484
PMID:39041344
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11263977/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer-associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF-derived extracellular vesicle (EV)-packaged long non-coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV-packaged lncRNA RP11-161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA-A expression, a key component of antigen presentation. Mechanistically, RP11-161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4-NOT complex, enhancing the degradation of HLA-A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti-tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA-based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF-derived EV-packaged lncRNA RP11-161H23.5/CNOT4/HLA-A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.

摘要

胰腺导管腺癌 (PDAC) 的特征是免疫逃避，这导致了预后不良。癌相关成纤维细胞 (CAF) 在协调 PDAC 肿瘤微环境中起着关键作用。我们研究了 CAF 衍生的细胞外囊泡 (EV) 包装的长非编码 RNA (lncRNA) 在免疫逃避中的作用，并探索了使用工程化 EV 加载小干扰 RNA (siRNA) 的基因治疗作为一种潜在的治疗策略。我们的研究结果强调了 CAF 来源的 EV 包装 lncRNA RP11-161H23.5 在促进 PDAC 免疫逃避中的重要性，其通过下调抗原呈递的关键组成部分 HLA-A 表达来实现。从机制上讲，RP11-161H23.5 与 CNOT4 形成复合物，后者是 mRNA 脱腺苷酶 CCR4-NOT 复合物的一个亚基，通过缩短其 poly(A) 尾巴增强 HLA-A mRNA 的降解。这种免疫逃避机制损害了抗肿瘤免疫反应。为了应对这一挑战，我们提出了一种利用工程化 EV 作为基于 siRNA 的基因治疗的天然和生物相容的纳米载体的创新方法，该策略有望提高免疫疗法在 PDAC 中的有效性。总体而言，我们的研究揭示了 CAF 衍生的 EV 包装 lncRNA RP11-161H23.5/CNOT4/HLA-A 轴在 PDAC 免疫逃避中的关键作用，并为治疗干预提供了新的途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7c068c1b8afa/JEV2-13-e12484-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/b6537635040e/JEV2-13-e12484-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/431bd2e479b5/JEV2-13-e12484-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7fd8bca35927/JEV2-13-e12484-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7e7fd048bd80/JEV2-13-e12484-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/81b8826cb6c1/JEV2-13-e12484-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7c068c1b8afa/JEV2-13-e12484-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/b6537635040e/JEV2-13-e12484-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/045debf9d746/JEV2-13-e12484-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/431bd2e479b5/JEV2-13-e12484-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/0d752df44bb6/JEV2-13-e12484-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7fd8bca35927/JEV2-13-e12484-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7e7fd048bd80/JEV2-13-e12484-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/81b8826cb6c1/JEV2-13-e12484-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2bf2/11263977/7c068c1b8afa/JEV2-13-e12484-g004.jpg

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