Gaetane Nocturne1, Saida Boudaoud2, Bineta Ly2, Juliette Pascaud2, Audrey Paoletti2, Xavier Mariette3. 1. INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. Electronic address: gaetane.nocturne@aphp.fr. 2. INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France. 3. INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.
Abstract
OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti-lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity. METHODS: NK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed. RESULTS: Exposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5-32.9] vs 31.3% [21.5-49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9-25.9] vs to 29.7% [22.5-43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling. CONCLUSIONS: Thus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.
OBJECTIVES:Rheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti-lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity. METHODS: NK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed. RESULTS: Exposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5-32.9] vs 31.3% [21.5-49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9-25.9] vs to 29.7% [22.5-43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling. CONCLUSIONS: Thus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.
Authors: Gregory S Calip; Pritesh R Patel; Sruthi Adimadhyam; Shan Xing; Zhaoju Wu; Karen Sweiss; Glen T Schumock; Todd A Lee; Brian C-H Chiu Journal: Int J Cancer Date: 2018-04-16 Impact factor: 7.396
Authors: Amandine Pradier; Maria Papaserafeim; Ning Li; Anke Rietveld; Charlotte Kaestel; Lyssia Gruaz; Cédric Vonarburg; Rolf Spirig; Gisella L Puga Yung; Jörg D Seebach Journal: Front Immunol Date: 2019-03-27 Impact factor: 7.561