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利用工程化细胞外囊泡将免疫调节剂直接递送至肿瘤浸润淋巴细胞。

Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.

作者信息

Lyu Xiabing, Yamano Tomoyoshi, Nagamori Kanto, Imai Shota, Van Le Toan, Bolidong Dilireba, Ueda Makie, Warashina Shota, Mukai Hidefumi, Hayashi Seigo, Matoba Kazutaka, Nishino Taito, Hanayama Rikinari

机构信息

WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kanazawa, Japan.

Department of Immunology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

出版信息

J Extracell Vesicles. 2025 Apr;14(4):e70035. doi: 10.1002/jev2.70035.

DOI:10.1002/jev2.70035
PMID:40154979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11952836/
Abstract

Extracellular vesicles (EVs) are important mediators of cell-cell communication, including immune regulation. Despite the recent development of several EV-based cancer immunotherapies, their clinical efficacy remains limited. Here, we created antigen-presenting EVs to express peptide-major histocompatibility complex (pMHC) class I, costimulatory molecule and IL-2. This enabled the selective delivery of multiple immune modulators to antigen-specific CD8 T cells, promoting their expansion in vivo without severe adverse effects. Notably, antigen-presenting EVs accumulated in the tumour microenvironment, increasing IFN-γ CD8 T cell and decreasing exhausted CD8 T cell numbers, suggesting that antigen-presenting EVs transformed the 'cold' tumour microenvironment into a 'hot' one. Combination therapy with antigen-presenting EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumours. We successfully engineered humanized antigen-presenting EVs, which selectively stimulated tumour antigen-specific CD8 T cells. In conclusion, engineering EVs to co-express multiple immunomodulators represents a promising method for cancer immunotherapy.

摘要

细胞外囊泡（EVs）是细胞间通讯的重要介质，包括免疫调节。尽管最近基于EVs的几种癌症免疫疗法有所发展，但其临床疗效仍然有限。在此，我们创建了表达I类肽-主要组织相容性复合体（pMHC）、共刺激分子和白细胞介素-2的抗原呈递EVs。这使得多种免疫调节剂能够选择性地递送至抗原特异性CD8 T细胞，促进其在体内扩增且无严重不良反应。值得注意的是，抗原呈递EVs在肿瘤微环境中积聚，增加了IFN-γ CD8 T细胞数量并减少了耗竭性CD8 T细胞数量，这表明抗原呈递EVs将“冷”肿瘤微环境转变为“热”肿瘤微环境。抗原呈递EVs与抗PD-1的联合治疗显示出针对已建立肿瘤的增强抗癌免疫力。我们成功构建了人源化抗原呈递EVs，其可选择性刺激肿瘤抗原特异性CD8 T细胞。总之，工程化EVs以共表达多种免疫调节剂是一种有前景的癌症免疫治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/8b000c9b5cb6/JEV2-14-e70035-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/fb6fb2866e51/JEV2-14-e70035-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/3ab5343d13af/JEV2-14-e70035-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/da8f42eb46db/JEV2-14-e70035-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/9ddd5d88d053/JEV2-14-e70035-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/788b2e7a24aa/JEV2-14-e70035-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/0052139bddc8/JEV2-14-e70035-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/8b000c9b5cb6/JEV2-14-e70035-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/fb6fb2866e51/JEV2-14-e70035-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/3ab5343d13af/JEV2-14-e70035-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/da8f42eb46db/JEV2-14-e70035-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/9ddd5d88d053/JEV2-14-e70035-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/788b2e7a24aa/JEV2-14-e70035-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/0052139bddc8/JEV2-14-e70035-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a75/11952836/8b000c9b5cb6/JEV2-14-e70035-g008.jpg

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