CD8型
MHC I级
生物
免疫学
抗原呈递
主要组织相容性复合体
肿瘤微环境
T细胞
促炎细胞因子
细胞毒性T细胞
免疫系统
癌症研究
炎症
遗传学
体外
作者
Jan D. Beck,Mustafa Diken,M Suchan,Michael Streuber,Elif Diken,Laura Kolb,Lisa Allnoch,Fulvia Vascotto,Daniel T. Peters,Tim Beißert,Özlem Akilli‐Öztürk,Özlem Türeci,Sebastian Kreiter,Mathias Vormehr,Uğur Şahin
出处
期刊:Cancer Cell
[Elsevier]
日期:2024-04-01
卷期号:42 (4): 568-582.e11
被引量:6
标识
DOI:10.1016/j.ccell.2024.02.013
摘要
Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying β2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8+ T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.
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