Correct stimulation of CD28H arms NK cells against tumor cells

Tumor evasion has recently been associated with a new member of the B7 family, HHLA2, mostly overexpressed on PDL1neg tumors. HHLA2 can either induce a costimulation signal when binding to CD28H or inhibition by binding to KIR3DL3 on T and NK cells. Given the broad distribution of CD28H on NK cells and its depicted role, we compare in this study two monoclonal antibodies targeting this new NK cell engager. We show that targeting CD28H at a specific epitope not only strongly activates Ca2+ flux but also results in NK cell activation. CD28H-activated NK cells further display increased cytotoxic activities against hematopoietic cell lines and bypass HHLA2 and HLA-E inhibitory signals. Additionally, scRNASeq analysis of clear cell kidney cancer cells (ccRCC) reveals that HHLA2+ ccRCC tumors are infiltrated with CD28H+NK cells which thus could be targeted by finely chosen anti-CD28H Abs.