The effects of agonistic α-4-1BB antibody on natural killer cell function

Abstract

Abstract 4-1BB is a member of the Tumor Necrosis Factor Receptor (TNFR) family. The TNFR family regulates a variety of functions including immune response, inflammation, and cell life/death. 4-1BB is a co-stimulatory molecule known best for its ability to increase survival, proliferation, anti-viral/tumor effects on T cells, and thus is currently undergoing clinical trials. However, the effects of 4-1BB stimulation in other cell types, such as natural killer cells (NK), are not well studied. Using a murine cytomegalovirus (MCMV) infected mouse model, we investigated the effects of agonistic α-4-1BB antibody stimulation on NK cell function and its impact on viral resistance. We hypothesized that 4-1BB stimulation will induce robust activation and proliferation of NK cells, resulting in an increased resistance against MCMV. To the contrary, treatment of the α-4-1BB antibody increased viral burden on 4 days post infection (p.i.) with highly increased NK cell proportion in spleens and livers. Further studies showed higher viral burden on day 1.5 p.i. with a reduced NK cell frequency. This suggests that an uncontrolled viral replication due to low NK numbers on early days of MCMV infection allows rapid expansion of residual NK cells by day 4. In vitro, treatment with α-4-1BB along with α-FasL antibodies rescued NK cell reduction, indicating that the NK cell loss is induced by Fas-mediated death signaling. Taken together, our data demonstrates that 4-1BB stimulation induces cell death signaling in the NK cell population, and results in an impaired anti-viral response. Further studies will provide a more complete view of the effects of 4-1BB stimulation as a cancer therapeutic, and also into the mechanism of NK cell life/death through TNFR signaling.