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长效mRNA编码的白细胞介素-2可恢复MHC I类缺陷癌症患者的CD8+ T细胞新抗原免疫力
作者:小柯机器人 发布时间:2024/3/16 14:12:50

德国BioNTech SE公司Ugur Sahin等研究人员合作发现,长效mRNA编码的白细胞介素-2可恢复MHC I类缺陷癌症患者的CD8+ T细胞新抗原免疫力。该项研究成果于2024年3月14日在线发表在《癌细胞》杂志上。

通过研究β2-微球蛋白(B2M)缺失的小鼠肿瘤模型,研究人员发现主要组织相容性复合体(MHC)I类缺失会导致肿瘤微环境(TME)的大量免疫荒漠化以及对免疫、化疗和放疗的广泛抵抗。研究表明,使用长效mRNA编码的白细胞介素-2(IL-2)治疗可恢复免疫细胞浸润、IFNγ促进、高度促炎的TME特征,与肿瘤靶向单克隆抗体(mAB)联合使用可克服治疗耐药性。

令人意想不到的是,这种疗法的有效性是由释放IFNγ的CD8+ T细胞驱动的,这些细胞能识别由TME驻留的活化巨噬细胞交叉呈递的新抗原。在IL-2治疗下,这些巨噬细胞获得了增强的抗原呈递能力和其他与M1表型相关的特征。这些研究结果凸显了恢复新抗原特异性免疫反应在治疗MHC I类缺失型癌症中的重要性。

据了解,MHC I类抗原呈递缺陷是一种常见的癌症免疫逃逸机制,但人们对其机理影响和应对这一挑战的潜在策略仍然知之甚少。

附:英文原文

Title: Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers

Author: Jan D. Beck, Mustafa Diken, Martin Suchan, Michael Streuber, Elif Diken, Laura Kolb, Lisa Allnoch, Fulvia Vascotto, Daniel Peters, Tim Beiert, zlem Akilli-ztürk, zlem Türeci, Sebastian Kreiter, Mathias Vormehr, Ugur Sahin

Issue&Volume: 2024-03-14

Abstract: Major histocompatibility complex (MHC) class I antigen presentation deficiency isa common cancer immune escape mechanism, but the mechanistic implications and potentialstrategies 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 substantialimmune desertification of the tumor microenvironment (TME) and broad resistance toimmune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encodedinterleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatoryTME signature, and when combined with a tumor-targeting monoclonal antibody (mAB),can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatmentis 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-associatedfeatures under IL-2 treatment. Our findings highlight the importance of restoringneoantigen-specific immune responses in the treatment of cancers with MHC class Ideficiencies.

DOI: 10.1016/j.ccell.2024.02.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00057-6

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:38.585
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx