Epstein–Barr Virus–Induced Antitumor Immune Response May Be Harnessable

Infection with certain viruses, including Epstein–Barr virus (EBV), may prime cytotoxic T cells to react to tumor-associated antigens (TAA), which are nonmutant antigens preferentially expressed on cancer cells. Choi, Wang, and colleagues analyzed T cells from mice with B cells that constitutively expressed the EBV signaling protein LMP1. In these mice, the LMP1-expressing B cells elicited a cytotoxic T-cell response, which may be explained by a prior finding that LMP1 expression can upregulate MHC-I and MHC-II expression by B cells. Constitutive LMP1 expression led to upregulation of many genes encoding proteins that are sources of established TAAs, and further examination revealed CD8⁺ T-cell responses to TAAs from two of the best-characterized TAA sources (survivin and ephrin type-A receptor 2). In experiments using ectopic expression of TRP1 (another known source of TAAs) in LMP1-expressing B cells, it was shown that TAAs are presented by both MHC-I and MHC-II, and MHC-II expression took place mostly through the endogenous pathway rather than as a result of TAA release from B cells followed by uptake and processing. In mouse B-cell lymphoma cells, expression of LMP1 caused an expected upregulation of MHC-II along with costimulatory ligands, including the CD8⁺ cytotoxic T-cell activating ligand CD80 and the CD4⁺ cytotoxic T-cell activating ligands CD70 and OX40L. Notably, naïve CD4⁺ cytotoxic T cells cultivated with LMP1-expressing mouse B-cell lymphoma cells caused expansion of the CD4⁺ T cells, which exhibited specific cytotoxicity toward non–LMP1 expressing B-cell lymphoma cells but not normal B cells. In vivo, These CD4⁺ cytotoxic T cells restricted B-cell lymphoma growth, whereas naïve CD4⁺ cytotoxic T cells did not, an effect that was enhanced by PD-1 blockade. Ectopic expression of LMP1 in tumor B cells from patients with chronic lymphocytic leukemia with the intent of priming T cells was shown to be a feasible approach to produce autologous CD4⁺ T cells specific to endogenous tumor antigens, including TAAs, demonstrating the potential therapeutic relevance of these findings.

Choi IK, Wang Z, Ke Q, Hong M, Paul Jr DW, Fernandes SM, et al. Mechanism of EBV inducing anti-tumour immunity and its therapeutic use. Nature 2020 Dec 23 [Epub ahead of print].

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