T cell-mediated immune surveillance conferred by latent Epstein-Barr virus genes suppresses a broad spectrum of tumor formation through NKG2D-NKG2DL interactions

Yuqi Jin¹Yun Guo¹Yohei Kawano¹Megumi Sasatani²Shun Ohki¹Yumi Tamura¹Yusuke Sotomaru³Yoshihiro Baba⁴Tomoharu Yasuda^1*

• ¹Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
• ²Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
• ³Natural Science Center for Basic Reseach and Development, Hiroshima University, Higashihiroshima, Hiroshima, Japan
• ⁴Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan

Epstein-Barr virus (EBV)-infected B cells effectively induce T cell-mediated immune surveillance that suppresses the proliferation of EBV + B cells and development of lymphomas.However, it remains unclear whether EBV-specific T cells are involved in the surveillance of EBVnegative general tumors. To address this issue, we induced immune surveillance by expressing key EBV antigens, LMP1 and LMP2A, in germinal center B cells and investigated the formation of non-B cell tumors. LMP1/2A mice showed a significantly reduced incidence of radiation-induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) even in the absence of LMP antigens in tumor cells and an extended life-span compared to control mice. LMP1/2A mice showed significantly higher numbers of activated memory T cells in both CD4 + and CD8 + αβT cell fractions compared to controls, suggesting their role in the elimination of tumor cells. Despite nearly absent MHC class I expression, tumor cells were effectively killed by CD8 + T cells activated upon LMP1/2A-expressing B cells. Transcriptome analysis identified upregulation of the NKG2D-NKG2DL pathway, emphasizing the capacity of LMP1/2A-induced T cells in the recognition of common tumor specific antigens. Moreover, not only T-cell tumors, but also intestinal tumors caused by Apc Min mutation were significantly suppressed by the LMP1/2A-induced immune surveillance. These results suggest that LMP1/2A-expression associated with EBV infection contributes to pan-tumor surveillance, implicating a beneficial aspect of EBV infection in humans and providing important insights into cancer prevention.