Janus kinase inhibitors alter NK cells phenotype and inhibit their antitumor capacity.

OBJECTIVE: Janus kinase inhibitors (JAKi) are efficacious in rheumatoid arthritis (RA) but concerns regarding the risk of cancer associated with their exposure have recently emerged. Given the role of NK cells in antitumor response, we investigated the impact of JAKi [tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA) and filgotinib (FIL)] on NK cells.

METHODS: We first performed ex vivo phenotype of NK cells in RA patients treated with TOFA, BARI or methotrexate (MTX). We next phenotyped sorted NK cells from healthy donors cultured with four JAKi or DMSO at three concentrations including the licensed dose [therapeutic concentration (therap)]. Thirdly, we assessed NK cells function using anti-NKp30 crosslinking and cocultures with two different tumor cell lines: A549 and SU-DHL-4.

RESULTS: Twenty-eight RA patients were included. Patients treated with TOFA had reduced expression of CD69 on NK cells compared with MTX (p< 0.05). We confirmed in vitro the negative impact of JAKi on NK cells maturation (CD57), activation (CD69), and activating receptor (NKp30), these two latter being specifically altered with TOFA and UPA. When NK cells were stimulated by NKp30, we observed reduced CD107a (p< 0.01) and IFNγ/TNF expression (p< 0.05) with TOFA. Lastly, NK cells exposed to TOFA showed reduced CD107a (p< 0.05) and altered cytotoxicity (p< 0.05) when cocultured with the two cell lines.

CONCLUSION: JAKi have a phenotypic and functional impact on NK cells activation and impair their antitumor activity with a variable impact depending on the JAKi. It remains an open question whether this mechanism can explain the increased tumor risk observed with TOFA.