Tumour-associated antigens (TAAs) comprise a large set of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as targets for immunotherapy has been explored for more than two decades1, yet the origins of TAA-specific T cells remain unclear. While tumour cells may be an important source of TAAs for T cell priming2, several recent studies suggest that infection with some viruses, including Epstein-Barr virus and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs3,4. However, the cellular and molecular basis of such responses remains undefined. Here we show that expression of the Epstein-Barr virus signalling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signalling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on major histocompatibility complex classes I (MHC-I) and II (MHC-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 mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in tumour B cells from patients with cancer and thereby enabling them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a wide range 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 to treatment of cancers.

中文翻译：

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EBV诱导抗肿瘤免疫的机制及其治疗用途

肿瘤相关抗原 (TAA) 包括一大组非突变细胞抗原，可被人和鼠癌症中的 T 细胞识别。它们作为免疫治疗靶点的潜力已经被探索了二十多年1，但 TAA 特异性 T 细胞的起源仍不清楚。虽然肿瘤细胞可能是 T 细胞启动的 TAA 的重要来源 2，但最近的几项研究表明，感染某些病毒，包括 Epstein-Barr 病毒和流感病毒，可以引发 T 细胞对异常表达的细胞抗原的反应，这些抗原作为 TAAs3,4 起作用。然而，这种反应的细胞和分子基础仍未确定。在这里我们展示了 Epstein-Barr 病毒信号蛋白 LMP1 在 B 细胞中的表达会激发 T 细胞对多种 TAA 的反应。LMP1 信号导致许多以前被证明是 TAA 的细胞抗原的过度表达，它们在主要组织相容性复合体 I (MHC-I) 和 II (MHC-II) 类（主要通过内源性途径）上的呈现以及共刺激配体 CD70 和OX40L，从而诱导有效的细胞毒性 CD4 + 和 CD8 + T 细胞反应。这些发现描绘了感染诱导的抗肿瘤免疫的机制。此外，通过在癌症患者的肿瘤 B 细胞中异位表达 LMP1，从而使它们能够引发 T 细胞，我们开发了一种通用方法，用于快速产生针对各种内源性肿瘤抗原（如 TAA）的自体细胞毒性 CD4 + T 细胞和新抗原，用于治疗 B 细胞恶性肿瘤。