先天rig - 1信号恢复肿瘤中的抗原呈递并克服T细胞抵抗。

IF 4.1 Q2 CELL BIOLOGY
Beatrice Thier, Annette Paschen
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引用次数: 0

摘要

近年来,免疫调节抗体治疗,称为免疫检查点阻断(ICB),已经彻底改变了晚期转移性黑色素瘤的治疗,在一个亚组患者中产生了持久的临床反应。但是,尽管取得了这些显著的进展,对治疗的耐药性仍然是一个重大的临床挑战。ICB的疗效严重依赖于细胞毒性CD8+ T细胞以HLA-I类(HLA-I)抗原依赖的方式靶向肿瘤细胞。黑色素瘤细胞中HLA-I抗原加工和递呈机制(HLA-I APM)的转录抑制导致HLA-I低/阴性肿瘤细胞表型逃避CD8+ T细胞识别并促进ICB抵抗。一般来说,HLA-I低/阴性肿瘤细胞可以通过干扰素(IFN)对T细胞重新敏感,增加HLA-I APM的表达。然而,当黑色素瘤细胞获得对IFN的耐药性时,这种机制就失效了,IFN最近被证明是除了HLA-I APM抑制外,ICB的关键耐药机制。为了寻找克服这些障碍的策略,我们确定了一种新的机制,可以恢复肿瘤细胞中独立于IFN的hla - 1抗原呈递(Such et al. (2020) J clininvest, doi: 10.1172/JCI131572)。我们证明,在患者源性ifn耐药黑色素瘤细胞中,肿瘤细胞通过其合成配体3pRNA对胞质先天免疫受体RIG-I的内在激活克服了转录HLA-I APM抑制。从头开始hla - 1 APM的表达是IRF1/ irf3依赖性的,并且使黑色素瘤细胞对自体细胞毒性CD8+ T细胞再敏感。值得注意的是,合成RIG-I配体和ICB在T细胞活化中协同作用,表明联合治疗可能是改善黑色素瘤患者预后的有效策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance.

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance.

In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such et al. (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. De novo HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.

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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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