Mechanism of EBV inducing anti-tumour immunity and its therapeutic use.
Mechanism of EBV inducing anti-tumour immunity and its therapeutic use.
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EB病毒诱导抗肿瘤免疫的机制及其治疗应用
DOI：
10.1038/s41586-020-03075-w
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发表时间：
2021-03
期刊：
影响因子：
64.8
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Choi IK;Wang Z;Ke Q;Hong M;Paul DW Jr;Fernandes SM;Hu Z;Stevens J;Guleria I;Kim HJ;Cantor H;Wucherpfennig KW;Brown JR;Ritz J;Zhang B
肿瘤相关抗原（TAA）包括人和鼠癌症中T细胞识别的大量非突变细胞抗原。它们作为免疫治疗靶点的潜力已经探索了二十多年，但TAA特异性T细胞的起源仍然难以捉摸。虽然肿瘤细胞可能是用于T细胞引发的TAA的重要来源，但最近的几项研究表明，包括EB病毒（EBV）和流感病毒在内的一些病毒的感染可以引发针对作为TAA的异常表达的细胞抗原的T细胞应答。然而，这种反应的细胞和分子基础仍然不确定。在这里，我们表明，在B细胞中EBV信号蛋白LMP 1的表达引起T细胞对多种TAA的反应。LMP 1信号传导导致许多先前显示为TAA的细胞抗原的过表达，它们在MHC-I和-II上的呈递（主要通过内源性途径），以及共刺激配体CD 70和OX 40 L的上调，从而诱导有效的细胞毒性CD 4+和CD 8 + T细胞应答。这些发现描绘了感染诱导的抗肿瘤免疫的新机制。此外，通过在患者肿瘤B细胞中异位表达LMP 1，从而使它们能够引发T细胞，我们开发了一种快速产生针对广泛的内源性肿瘤抗原（如TAA和新抗原）的自体细胞毒性CD 4 + T细胞的通用方法，用于治疗B细胞恶性肿瘤。这项工作强调需要重新审视有关病毒和肿瘤免疫的经典概念，这对于充分了解常见感染对人类健康的影响和改善癌症免疫方法的合理设计至关重要。
Tumour-associated antigens (TAAs) comprise a large collection of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as immunotherapy targets has been explored for over two decades, yet the genesis of TAA-specific T cells remains elusive. While tumour cells may be an important source of TAAs for T cell priming, several recent studies suggest that infection with some viruses including Epstein-Barr virus (EBV) and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs. However, the cellular and molecular basis of such responses remains undefined. Here, we show that expression of the EBV signaling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signaling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on MHC-I and -II (mainly through the endogenous pathway), and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a novel mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in patient tumour B cells and thereby empowering them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a broad array of endogenous tumour antigens, such as TAAs and neoantigens, for treating B-cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches for cancers.
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影响因子：
20.3
作者：
Cui, Yongzhi;Onozawa, Masahiro;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
6.7
作者：
Dunmire, Samantha K.;Grimm, Jennifer M.;Hogquist, Kristin A.
通讯作者：
Hogquist, Kristin A.
影响因子：
10.1
作者：
Iheagwara, Uzoma K.;Beatty, Pamela L.;Finn, Olivera J.
通讯作者：
Finn, Olivera J.
影响因子：
6.2
作者：
Yamaguchi, Shinjiro;Tatsumi, Tomohide;Hayashi, Norio
通讯作者：
Hayashi, Norio
DOI：
10.1073/pnas.88.8.3290
发表时间：
1991-04-01
影响因子：
11.1
作者：
BROOKS, A;HARTLEY, S;MCCLUSKEY, J
通讯作者：
MCCLUSKEY, J