EBV Type 1 versus Type 2: A determinant of NK cell anti-tumor activity in Burkitt lymphoma

Terminally differentiated CD56^negCD16^pos NK cells have been described after chronic viral and malaria infections, and in children diagnosed with Burkitt lymphoma (BL). Despite CD56^neg NK cells appearing to be poor at direct cytotoxicity, they express high levels of cytotoxic granules (i.e. granzymes, perforin), activation markers, and Fc-γ receptors (CD32 and CD16) that are typically engaged in antibody-dependent cell cytotoxicity (ADCC). In addition, the abundance of CD56^neg NK cells strongly correlates with IgG1 and IgG3 plasma levels, which are essential subclasses for ADCC. To determine whether CD56^neg NK cells have superior ADCC capacity relative to CD56^dim NK cells, we performed ADCC assays using effector cells from pediatric cancer patients and healthy children from malaria endemic regions of Kenya, targeting in vitro rituximab-treated commercial and newly established BL cell lines. We found that CD56^neg NK cells were indeed capable of in vitro ADCC, showing a significant increase of CD107a-mediated degranulation in the presence of rituximab; however, they were not as efficient as CD56^dim NK cells. Moreover, we found that the ADCC magnitude was significantly lower against EBV-Type 2 (EBV-T2) BL lines compared to EBV-Type 1 (EBV-T1). EBV-T2 tumor cell lines expressed significantly more lytic viral proteins than EBV-T1, making them more sensitive to direct cytotoxicity. Results from this study highlight the importance of assessing inter-patient variation in NK cell profiles in conjunction with ADCC sensitivity and EBV type within tumor cells when evaluating clinical outcomes for NK-mediated immunotherapies.