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JAK inhibitors alter NK cell functions and may impair immunosurveillance against lymphomagenesis

Cellular & Molecular Immunology volume 17, pages 552–553 (2020)Cite this article

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An increased risk of B cell lymphomas in patients with myeloproliferative neoplasm (MPN) treated with Janus kinase (JAK) inhibitors has recently been explored.1,2,3 In light of contradictory results, it is highly important to assess whether JAK inhibitors might be associated with a higher risk of lymphoma, notably in patients with pre-existing B cell clones that can escape immunosurveillance after exposure to JAK inhibitors.

This situation is very similar to what is observed in patients with autoimmune diseases, especially rheumatoid arthritis (RA). B cell clones are present in patients with RA, and dominant BCR clones in the peripheral blood predict the onset of the disease in at-risk individuals.4 In addition, RA patients have a 2–3-fold increased risk of lymphoma, and the impact of immunosuppressive drugs remains unclear. Tofacitinib, a JAK 1/3 inhibitor, has been approved for use in RA and, its use is increasing. To date, lymphomas have not been found to occur significantly more frequently in RA patients treated with tofacitinib. However, the frequency of their association with Epstein–Barr virus (EBV) has been found to be slightly increased compared to what is expected in RA patients.5 Thus the hypothesis is that JAK inhibitors might alter the control of B cell clones present in some MPN or RA patients and might promote the occurrence of lymphomas in these at-risk patients. In this context, we aimed to better understand the cellular targets of tofacitinib, focusing on natural killer (NK) cells, which are cellular actors of antitumor immunosurveillance, to anticipate the safety profile of the drug. We assessed the impact of tofacitinib on the phenotype and function of NK cells. NK cells isolated from healthy blood donors were cultured in interleukin (IL)-2 in the presence of tofacitinib at 3 concentrations (10, 50, and 100 nM) or control for 6 days. The 50 and 100 nM doses of tofacitinib in vitro were equivalent to the 5 and 10 mg doses, respectively, used BID (twice daily) for human RA, and 10 nM tofacitinib represented a subtherapeutic dose for RA treatment.6 At the end of culture, NK cells were phenotyped. First, we observed that tofacitinib was not cytotoxic to NK cells regardless of the concentration. However, tofacitinib significantly decreased IL-2-induced activation, as assessed by CD69 expression. In addition, exposure to tofacitinib (50 and 100 nM) led to decreased expression of natural cytotoxic receptors, including NKp44 and NKp30 but not NKp46. NKG2D expression was also decreased following exposure to tofacitinib at the highest concentration. Finally, 100 nM tofacitinib blocked the maturation of NK cells, as assessed by decreased CD57 and Tim-3 expression.

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Acknowledgements

Grants were obtained from Fondation pour la Recherche Médicale (DEQ20150934719: Sjögren’s syndrome and autoimmunity-associated lymphomas (SAIL). Grants were also obtained from Pfizer (“Assessment of the risk of lymphoproliferative disorders associated with specific inhibition of the JAK pathway_modified,” #IIR WI199662 and “JAKinNaK: Assessment of the impact of different JAK inhibitors on NK cell functions”, #WI236322).

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Authors and Affiliations

  1. INSERM UMR 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France

    Gaetane Nocturne, Juliette Pascaud, Bineta Ly, Farhad Tahmasebi & Xavier Mariette

  2. Department of Rheumatology, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Paris, France

    Gaetane Nocturne & Xavier Mariette

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  1. Gaetane Nocturne
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  2. Juliette Pascaud
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Contributions

G.N., J.P., B.L., and F.T. performed the experiments; G.N. and X.M. analyzed the results, designed the research, and wrote the paper.

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Correspondence to Gaetane Nocturne.

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X.M. received an honorarium from Pfizer.

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Nocturne, G., Pascaud, J., Ly, B. et al. JAK inhibitors alter NK cell functions and may impair immunosurveillance against lymphomagenesis. Cell Mol Immunol 17, 552–553 (2020). https://doi.org/10.1038/s41423-019-0320-3

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