EBNA1 inhibitors with lytic induction activity can sensitize natural killer cells to mediate the killing of nasopharyngeal carcinoma cells

Nasopharyngeal carcinoma (NPC) is endemic in South China areas, including Guangdong Province. One of the causing factors for NPC is EBV infection. Upon infection, EBV proteins such as LMP1 activates pro-oncogenic signaling pathways and contributes the malignant growth of the tumor cells. EBNA1 is the sole protein ubiquitously expressed in all EBV-related diseases and the functional form of EBNA1 occurs as a homodimer. EBNA1 functions to maintain the propagation of EBV genome in the host cells. Our group previously developed a panel of EBNA1-inhibiting peptide probes, which was found to disrupt the latent infection of EBV and induced lytic activation in the NPC tumor cells. We hypothesized that the lytic induction will disrupt the phenotype of the cancer cells and sensitize them for killing by the immune cells. In this study, we studied the effect of those EBNA1-targeted probes on the NK cell mediated killing of NPC cells and examined the potential of activating the NK cells of NPC patients for the management of NPC. Results showed that after drug treatment, type I interferons (IFNα and IFNβ) production by the cancer cells were induced, via a LMP1-NFκB signaling axis. As type I interferons have been reported to activated the NK cells, we are exploring the effects of such induction of interferons on the NK cell mediated killing. At the same time, by comparing the NPC patients derived NK cells with healthy donors derived NK cells, we found that the NK cells derived from NPC patients are fully functional and can be utilized for the management of NPC. Our study showed that anti-EBNA1 probes could sensitize the NPC cells for killing by the NK cells.