Allogeneic tumor cell-derived extracellular vesicles stimulate CD8 T cell response in colorectal cancer.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-09-16 eCollection Date: 2023-12-19 DOI:10.1016/j.omto.2023.100727
Travis J Gates, Dechen Wangmo, Xianda Zhao, Subbaya Subramanian
{"title":"Allogeneic tumor cell-derived extracellular vesicles stimulate CD8 T cell response in colorectal cancer.","authors":"Travis J Gates, Dechen Wangmo, Xianda Zhao, Subbaya Subramanian","doi":"10.1016/j.omto.2023.100727","DOIUrl":null,"url":null,"abstract":"<p><p>Most colorectal cancer (CRC) patients present with a microsatellite-stable phenotype, rendering them resistant to immune checkpoint inhibitors (ICIs). Among the contributors to ICI resistance, tumor-derived extracellular vesicles (TEVs) have emerged as critical players. Previously we demonstrated that autologous transfer of TEVs without miR-424 can induce tumor antigen-specific immune responses in CRC models. Therefore, we postulated that allogeneic TEVs, modified to lack miR-424 and derived from an MC38 cells, could induce CD8<sup>+</sup> T cell responses while restraining CT26 cell-based tumor. Here, we show that prophylactic administration of MC38 TEVs, without miR-424, showed a significant augmentation in CD8<sup>+</sup> T-cells within CT26 tumors. This allogenic TEV effect was evident in CT26 tumors but not B16-F10 melanoma. Furthermore, we demonstrated the capacity of dendritic cells (DCs) to internalize TEVs, a possible mechanism to elicit immune response. Our investigation of autologously administered DCs, which had been exposed to modified TEVs, underscores their potential to dampen tumor growth while elevating CD8<sup>+</sup> T cell levels vis-a-vis MC38 wild-type TEVs exposed to DCs. Notably, the modified TEVs were well tolerated and did not increase peripheral blood cytokine levels. Our findings underscore the potential of modified allogeneic TEVs without immune-suppressive factors to elicit robust T cell responses and limit tumor growth.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2023-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562189/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy Oncolytics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.omto.2023.100727","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/19 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Most colorectal cancer (CRC) patients present with a microsatellite-stable phenotype, rendering them resistant to immune checkpoint inhibitors (ICIs). Among the contributors to ICI resistance, tumor-derived extracellular vesicles (TEVs) have emerged as critical players. Previously we demonstrated that autologous transfer of TEVs without miR-424 can induce tumor antigen-specific immune responses in CRC models. Therefore, we postulated that allogeneic TEVs, modified to lack miR-424 and derived from an MC38 cells, could induce CD8+ T cell responses while restraining CT26 cell-based tumor. Here, we show that prophylactic administration of MC38 TEVs, without miR-424, showed a significant augmentation in CD8+ T-cells within CT26 tumors. This allogenic TEV effect was evident in CT26 tumors but not B16-F10 melanoma. Furthermore, we demonstrated the capacity of dendritic cells (DCs) to internalize TEVs, a possible mechanism to elicit immune response. Our investigation of autologously administered DCs, which had been exposed to modified TEVs, underscores their potential to dampen tumor growth while elevating CD8+ T cell levels vis-a-vis MC38 wild-type TEVs exposed to DCs. Notably, the modified TEVs were well tolerated and did not increase peripheral blood cytokine levels. Our findings underscore the potential of modified allogeneic TEVs without immune-suppressive factors to elicit robust T cell responses and limit tumor growth.

Abstract Image

Abstract Image

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
同种异体肿瘤细胞来源的细胞外囊泡刺激CD8 T细胞在结直肠癌中的应答。
大多数癌症(CRC)患者表现为微卫星型表型,使其对免疫检查点抑制剂(ICIs)具有耐药性。在ICI耐药性的贡献者中,肿瘤衍生的细胞外小泡(TEV)已成为关键参与者。先前我们证明,在CRC模型中,不含miR-424的TEV的自体转移可以诱导肿瘤抗原特异性免疫反应。因此,我们假设,经修饰为缺乏miR-424并来源于MC38细胞的异基因TEV可以诱导CD8+T细胞反应,同时抑制基于CT26细胞的肿瘤。在这里,我们发现预防性给予MC38 TEV,不含miR-424,显示CT26肿瘤内CD8+T细胞显著增加。这种同种异体TEV效应在CT26肿瘤中明显,但在B16-F10黑色素瘤中不明显。此外,我们证明了树突状细胞(DC)内化TEV的能力,这是引发免疫反应的可能机制。我们对暴露于修饰的TEV的自体给药DC的研究强调了它们抑制肿瘤生长的潜力,同时相对于暴露于DC的MC38野生型TEV提高CD8+T细胞水平。值得注意的是,经修饰的TEV具有良好的耐受性,并且不会增加外周血细胞因子水平。我们的研究结果强调了在没有免疫抑制因子的情况下修饰异基因TEV引发强大的T细胞反应和限制肿瘤生长的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
期刊最新文献
Targeting mesothelin in cancer New advances in cancer therapy targeting TGF-β signaling pathways miR-146a: Overcoming coldness in ovarian cancer Thank you to our 2023 reviewers Gaining insights into virotherapy with canine models
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1