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EBV infection in epithelial malignancies induces resistance to the anti-tumor function of natural killer cells via CD73-mediated metabolism of AMP [NK cells]

ABSTRACT: CD73 is a metabolic immune checkpoint that regulates the homeostatic balance of adenosine levels in the tumor microenvironment (TME). However, the regulation of CD73 abnormal expression by Epstein-Barr virus (EBV) in EBV-associated malignancies and its immune editing mechanism on natural killer (NK) cells remains unclear. In this study, we demonstrate that CD73 is upregulated in EBV-associated malignancies and is negatively correlated with the anti-tumor activity of NK cells. Mechanistically, the EBV latent protein LMP2A upregulates CD73 expression through the PI3K/AKT signaling pathway, and the metabolic product of CD73, adenosine, negatively regulates the anti-tumor function of NK cells through multiple signaling pathways. Furthermore, targeted knockout of CD73, small molecule inhibitor, or neutralizing antibody combined with adoptive transfer of NK cells significantly improved the treatment efficacy for EBV-positive nasopharyngeal carcinoma (NPC). Importantly, we also found abnormal upregulation of CD73 in EBV-positive lymphoma, gastric cancer and lung cancer. In summary, our research identifies the mechanism of immune evasion of NK cell anti-tumor function in EBV-associated malignancies through the abnormal expression of CD73, and targeting CD73 combined with adoptive transfer of NK cells may provide a new strategy for immunotherapy of EBV-related malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309453 | GEO | 2026/07/23

REPOSITORIES: GEO

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EBV infection in epithelial malignancies induces resistance to the anti-tumor function of natural killer cells via CD73-mediated metabolism of AMP [cell line]

Project description:CD73 is a metabolic immune checkpoint that regulates the homeostatic balance of adenosine levels in the tumor microenvironment (TME). However, the regulation of CD73 abnormal expression by Epstein-Barr virus (EBV) in EBV-associated malignancies and its immune editing mechanism on natural killer (NK) cells remains unclear. In this study, we demonstrate that CD73 is upregulated in EBV-associated malignancies and is negatively correlated with the anti-tumor activity of NK cells. Mechanistically, the EBV latent protein LMP2A upregulates CD73 expression through the PI3K/AKT signaling pathway, and the metabolic product of CD73, adenosine, negatively regulates the anti-tumor function of NK cells through multiple signaling pathways. Furthermore, targeted knockout of CD73, small molecule inhibitor, or neutralizing antibody combined with adoptive transfer of NK cells significantly improved the treatment efficacy for EBV-positive nasopharyngeal carcinoma (NPC). Importantly, we also found abnormal upregulation of CD73 in EBV-positive lymphoma, gastric cancer and lung cancer. In summary, our research identifies the mechanism of immune evasion of NK cell anti-tumor function in EBV-associated malignancies through the abnormal expression of CD73, and targeting CD73 combined with adoptive transfer of NK cells may provide a new strategy for immunotherapy of EBV-related malignancies.

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