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+) 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+ 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+ 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 membrane 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 upregulation 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.

中文翻译：

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EBV 上调的 B7-H3 抑制 NK 细胞介导的抗肿瘤功能并促进鼻咽癌进展

鼻咽癌（NPC）是一种与 Epstein-Barr 病毒（EBV）相关的上皮恶性肿瘤，其特征是存在明显的淋巴细胞浸润，包括自然杀伤（NK）细胞。尽管 NK 细胞可以不受 MHC 限制直接靶向 EBV 感染的肿瘤细胞，但 EBV 阳性 (EBV+) NPC 细胞通常会产生抵抗机制，使它们能够逃避 NK 细胞的免疫监视。阐明 EBV 诱导的 NK 细胞功能障碍的机制将有助于设计新的基于 NK 细胞的免疫疗法来治疗鼻咽癌。在此，我们证实了 EBV+ NPC 组织中 NK 细胞的细胞毒功能受损，并发现 EBV 感染诱导的 NPC 中 B7-H3 的表达与 NK 细胞功能呈负相关。体外和体内阐明了 B7-H3 的 EBV+ 肿瘤表达对 NK 细胞功能的抑制作用。从机制上讲，通过 EBV 潜伏膜蛋白 1 (LMP1) 激活 PI3K/AKT/mTOR 信号通路是 EBV 感染诱导 B7-H3 表达上调的原因。在采用原代 NK 细胞过继转移的 NPC 异种移植小鼠模型中，肿瘤细胞上 B7-H3 的缺失结合抗 PD-L1 治疗恢复了 NK 细胞介导的抗肿瘤活性，并显着提高了 NK 细胞的抗肿瘤功效。根据我们的调查结果，