Expression and function of Kv1.3 channel in malignant T cells in Sézary syndrome

// Tengpeng Hu 1 , Terkild Brink Buus 1 , Thorbjorn Krejsgaard 1 , Anneline Nansen 2 , Betina Kerstin Lundholt 2 , Pieter Spee 3 , Simon Fredholm 1 , David Leander Petersen 1 , Edda Blumel 1 , Maria Gluud 1 , Madalena N. Monteiro 1 , Andreas Willerslev-Olsen 1 , Mads Hald Andersen 1 , 4 , Per thor Straten 1 , 4 , Ozcan Met 1 , 4 , Veronica Stolearenco 1 , Hanne Fogh 5 , Robert Gniadecki 5 , Claudia Nastasi 1 , Thomas Litman 1 , Anders Woetmann 1 , Lise Mette Rahbek Gjerdrum 6 and Niels Odum 1 1 LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark 2 Department of Molecular Pharmacology, Zealand Pharma A/S, Glostrup, Denmark 3 PS Pharmaconsult, Allerod, Denmark 4 Center for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital at Herlev, Copenhagen, Denmark 5 Department of Dermatology, Copenhagen University Hospital at Bispebjerg, Copenhagen, Denmark 6 Department of Pathology, Zealand University Hospital, Roskilde, Denmark Correspondence to: Niels Odum, email: ndum@sund.ku.dk Keywords: Sezary syndrome; Kv1.3 channel; ShK; cutaneous T-cell lymphoma; cancer Received: March 11, 2019     Accepted: July 15, 2019     Published: August 06, 2019 ABSTRACT The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed by a subset of chronically activated memory T cells and plays an important role in their activation and proliferation. Here, we show that primary malignant T cells isolated from patients with Sezary syndrome (SS) express Kv1.3 and are sensitive to potent Kv1.3 inhibitors ShK and Vm24, but not sensitive to a less potent inhibitor [N17A/F32T]-AnTx. Kv1.3 blockade inhibits CD3/CD28-induced proliferation and IL-9 expression by SS cells in a concentration-dependent manner. In parallel, CD3/CD28-mediated CD25 induction is inhibited, whereas Kv1.3 blockade has no effect on apoptosis or cell death as judged by Annexin V and PI staining. In conclusion, we provide the first evidence that malignant T cells in SS express functional Kv1.3 channels and that Kv1.3 blockade inhibits activation-induced proliferation as well as cytokine and cytokine receptor expression in malignant T cells, suggesting that Kv1.3 is a potential target for therapy in SS.