| Autor: |
Tong Xiang, Jiexia Zhang, Bo Zhu, Yan Xiong, Qinqin Ren, Guojun Liu, Chaopin Yang, Pingjuan Liu, Xiao Zhang, Shanshan Zhang, Xiang Zhou, Yingping Huang, Xiaohong Deng, Xiaobing Duan, Haiwen Chen |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2326-6066.c.6620941.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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