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

Yao, Hanming; Huang, Chengzhi; Zou, Jinmao; Liang, Weiling; Zhao, Yue; Yang, Kege; Zhong, Ziyi; Zhou, Shurui; Li, Jiajia; Li, Yaqing; Xu, Lishu; Huang, Kaihong; Lian, Guoda

Yao, Hanming; Huang, Chengzhi; Zou, Jinmao; Liang, Weiling; Zhao, Yue; Yang, Kege; Zhong, Ziyi; Zhou, Shurui; Li, Jiajia; Li, Yaqing; Xu, Lishu; Huang, Kaihong; Lian, Guoda.

Afiliación

Yao H; Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Huang C; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Zou J; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Liang W; Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Zhao Y; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Yang K; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Zhong Z; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Zhou S; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Li J; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Li Y; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Xu L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Huang K; Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Lian G; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

J Extracell Vesicles ; 13(7): e12484, 2024 Jul.

Article en En | MEDLINE | ID: mdl-39041344

ABSTRACT

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.

Asunto(s)

Fibroblastos Asociados al Cáncer; Carcinoma Ductal Pancreático; Vesículas Extracelulares; Antígenos HLA-A; Neoplasias Pancreáticas; ARN Largo no Codificante; Humanos; ARN Largo no Codificante/genética; ARN Largo no Codificante/metabolismo; Fibroblastos Asociados al Cáncer/metabolismo; Fibroblastos Asociados al Cáncer/inmunología; Vesículas Extracelulares/metabolismo; Vesículas Extracelulares/inmunología; Neoplasias Pancreáticas/inmunología; Neoplasias Pancreáticas/genética; Neoplasias Pancreáticas/terapia; Carcinoma Ductal Pancreático/inmunología; Carcinoma Ductal Pancreático/genética; Carcinoma Ductal Pancreático/terapia; Línea Celular Tumoral; Antígenos HLA-A/genética; Antígenos HLA-A/inmunología; Antígenos HLA-A/metabolismo; Evasión Inmune; Regulación Neoplásica de la Expresión Génica; Regulación hacia Abajo; ARN Interferente Pequeño; Microambiente Tumoral/inmunología; Animales; Escape del Tumor; Ratones

Palabras clave

CAFs; MHCI; engineered extracellular vesicles; immune evasion; lncRNA; pancreatic cancer

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Antígenos HLA-A / Carcinoma Ductal Pancreático / ARN Largo no Codificante / Vesículas Extracelulares / Fibroblastos Asociados al Cáncer Límite: Animals / Humans Idioma: En Revista: J Extracell Vesicles Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos

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