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

Abstract

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 verified 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.

Circulating Epstein-Barr virus DNA associated with hepatic impairment and its diagnostic and prognostic role in patients with gastric cancer

“…Although a tendency toward decreased platelets is frequently observed in acute EBV infection ( 30 ), we noted a substantially increased level of PLT in EBVaGC. In a recent study on nasopharyngeal carcinoma and EBVaGC, EBV was reported to induce F3-mediated PLT aggregation that inhibited the antitumor function of natural killer cells ( 31 ). In the current study, we also noted a tendency for an elevation in inflammatory CRP in EBVaGC.…”

Immunotherapeutic approaches in EBV-associated nasopharyngeal carcinoma

“…Our team has been actively developing new approaches and targets for the treatment of EBV-NPC. We found that after EBV infection, LMP2A induced the upregulation of F3 expression and was associated with the dysfunction of NK cells in NPC (2). We used a combination of F3 inhibitor and NK cell adoptive therapy and achieved a considerable therapeutic effect in a mouse model of NPC.…”

“…Approximately 95% of the global population are EBV asymptomatic carriers ( 1 , 2 ). EBV primarily infects epithelial and B cells.…”

“…NPC and EBVaGC are the two most common EBV-associated epithelial malignancies that account for 80% of these tumors. Over 90% of patients with confirmed undifferentiated NPC are infected with EBV ( 2 , 13 , 14 ). According to the last two global cancer statistical surveys from the International Agency for Research on Cancer, in 2018 and 2020, there were 129,079 and 133,354 new NPC cases in the world, and 72,987 and 80,008 NPC-associated deaths worldwide, respectively ( 15 , 16 ).…”

Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment

“…NKs can target EBV-infected cells that are in the lytic replication phase and maintain the homeostasis of the host immune system [43,44]. A recent study found that LMP2A inhibited NK cell function through platelet aggregation by platelet factor 3, which offers a novel candidate for the development of NK cell immunotherapy [45]. EBV miRNAs have been confirmed to mediate the escape of NK cell killing by down-regulating NKG2D ligand and target pro-apoptotic proteins such as PUMA to resist NK cell cytotoxity [46][47][48][49].…”