Correct stimulation of CD28H arms NK cells against tumor cells

Abstract Tumor evasion has recently been associated with a novel member of the B7 family, HERV‐H LTR‐associating 2 (HHLA2), which is mostly overexpressed in PDL‐1 neg tumors. HHLA2 can either induce a costimulation signal when bound to CD28H or inhibit it by binding to KIR3DL3 on T‐ and NK cells. Given the broad distribution of CD28H expression on NK cells and its role, we compared two monoclonal antibodies targeting this novel NK‐cell engager in this study. We show that targeting CD28H at a specific epitope not only strongly activates Ca 2+ flux but also results in NK‐cell activation. CD28H‐activated NK cells further display increased cytotoxic activity against hematopoietic cell lines and bypass HHLA2 and HLA‐E inhibitory signals. Additionally, scRNA‐seq analysis of clear cell renal cancer cells revealed that HHLA2 + clear cell renal cancer cell tumors were infiltrated with CD28H + NK cells, which could be targeted by finely chosen anti‐CD28H Abs.