EBV-Upregulated B7-H3 Inhibits NK cell-Mediated Antitumor Function and Contributes to Nasopharyngeal Carcinoma Progression

作者：Chen, Haiwen; Duan, Xiaobing; Deng, Xiaohong; Huang, Yingping; Zhou, Xiang; Zhang, Shanshan; Zhang, Xiao; Liu, Pingjuan; Yang, Chaopin; Liu, Guojun; Ren, Qinqin; Xiong, Yan; Zhu, Bo^*; Zhang, Jiexia^*; Xiang, Tong^*

来源：Cancer Immunology Research, 2023, 11(6): 830-846.

DOI：10.1158/2326-6066.CIR-22-0374

• EPSTEIN-BARR-VIRUS
• EXPRESSION
• PROTEINS
• MOLECULE
• GROWTH
• CANCER
• PD-L1
• LMP1

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy characterized by the presence of prominent infiltration of lymphocytes, including natural killer (NK) cells. Although NK cells can directly target EBV-infected tumor cells without restriction by the MHC, EBV-positive (EBV thorn ) NPC cells often develop resistance mechanisms that allow them to evade immune surveillance by NK cells. Elucidating the mechanisms involved in EBV-induced NK-cell dysfunction will contribute to the design of novel NK cell-based immunotherapies to treat NPC. Herein, we confirmed that the cytotoxic function of NK cells was impaired in EBV thorn NPC tissues and found that EBV infection-induced expression of B7-H3 in NPC negatively correlated with NK-cell function. The inhibitory effect of EBV thorn tumor expression of B7-H3 on NK-cell function was clarified in vitro and in vivo. Mechanistically, activation of the PI3K/AKT/mTOR signaling pathway via EBV latent mem-brane protein 1 (LMP1) was responsible for EBV infection- induced upregulation of B7-H3 expression. In an NPC xenograft mouse model with adoptive transfer of primary NK cells, deletion of B7-H3 on tumor cells in combination with anti-PD-L1 treatment restored NK cell-mediated antitumor activity and significantly improved the antitumor efficacy of NK cells. On the basis of our findings, we conclude that EBV infection can inhibit NK cell-mediated antitumor function by inducing upre-gulation of B7-H3 expression and provide a rationale for NK cell-based immunotherapies in combination of PD-L1 blockade and overcoming the immunosuppression of B7-H3 to treat EBV-associated NPC.

• 单位
  1; 中山大学; 广州中医药大学; 广州医学院