Inhibitory NKG2A and absent activating NKG2C NK cell responses are associated with the development of EBV lymphomas.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV Hodgkin (EBVHL) or non-Hodgkin lymphomas (EBVnHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBVHL and EBVnHL. Therefore, we recruited a study cohort of 63 EBVHL and EBVnHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV lymphoma patients exclusively the high-affine peptide variant-encoding EBV-strains reactivate. In EBVHL and EBVnHL patients, the high-expressing HLA-E0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 and HLA-E0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the spread of EBV-infected tumor cells. In addition, EBVHL and EBVnHL patients, showed impaired pro-inflammatory NKG2C NK cell responses, which accelerated the EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2ANKG2C NK cells. Thus, the HLA-E/NKG2A pathway and individual NKG2C NK cell responses are associated with the progression toward EBV lymphomas.