4.8 Article

EBV Infection in Epithelial Malignancies Induces Resistance to Antitumor Natural Killer Cells via F3-Mediated Platelet Aggregation

Journal

CANCER RESEARCH
Volume 82, Issue 6, Pages 1070-1083

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-2292

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Funding

  1. National Natural Science Foundation of China [81872228, 81874129, 82172795, 82103433]
  2. Guangdong Basic and Applied Basic Research Foundation [2020B1515020002, 2020A1515110013]
  3. Fundamental Research Funds for the Central Universities

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This study reveals a mechanism by which EBV-associated epithelial malignancies escape NK-cell-mediated immune surveillance, providing a new target for improving NK-cell immunotherapy.
Nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) are two major EBV-associated epithelial malignancies, both of which are characterized by the infiltration of a large number of lymphocytes, including natural killer (NK) cells. Although NK cells can prevent the development of EBV-associated epithelial malignancies, EBV-infected tumor cells often develop resistance to surveillance by NK cells. Elucidating the interactions between NK cells and EBV-infected tumor cells will facilitate the development of more effective NK-mediated therapies for treating EBV-associated malignancies. Here we investigated the cytotoxic function of NK cells in EBV-associated epithelial malignancies and discovered that EBV infection-induced upregulation of F3 expression correlates with NK-cell dysfunction in NPC and EBVaGC. The subsequent inhibitory effect of F3-mediated platelet aggregation on NK-cell function was ver- ified in vitro and in vivo. Mechanistically, EBV latent membrane protein 2A (LMP2A) mediated upregulation of F3 through the PI3K/AKT signaling pathway. In an NPC xenograft mouse model, inhibition of F3 restored the antitumor function of NK cells and showed therapeutic efficacy when administered with NK-cell transfer. On the basis of these findings, EBV infection induces F3-mediated platelet aggregation that inhibits the antitumor function of NK cells, providing a rationale for developing and combining NK-cell-based therapies with F3 inhibitors to treat EBV-associated epithelial malignancies. Significance: This study reveals a mechanism by which EBV-associated epithelial malignancies escape NK-cell-mediated immune surveillance, providing a new target for improving NK-cell immunotherapy.

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