Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56(+), but not CD56(-), NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56(+), but not CD56(-), NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56(+) NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56(+) NK cells. Thus, these results are the first to show that MMF augments CD56(+) NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.