title: Blocking KCa3.1 channels increases tumor cell killing by a subpopulation of human natural killer lymphocytes.
abstract: Natural killer (NK) cells are large granular lymphocytes that participate in both innate and adaptive immune responses against tumors and pathogens. They are also involved in other conditions, including organ rejection, graft-versus-host disease, recurrent spontaneous abortions, and autoimmune diseases such as multiple sclerosis. We demonstrate that human NK cells express the potassium channels Kv1.3 and KCa3.1. Expression of these channels does not vary with expression levels of maturation markers but varies between adherent and non-adherent NK cell subpopulations. Upon activation by mitogens or tumor cells, adherent NK (A-NK) cells preferentially up-regulate KCa3.1 and non-adherent (NA-NK) cells preferentially up-regulate Kv1.3. Consistent with this different phenotype, A-NK and NA-NK do not display the same sensitivity to the selective KCa3.1 blockers TRAM-34 and NS6180 and to the selective Kv1.3 blockers ShK-186 and PAP-1 in functional assays. Kv1.3 block inhibits the proliferation and degranulation of NA-NK cells with minimal effects on A-NK cells. In contrast, blocking KCa3.1 increases the degranulation and cytotoxicity of A-NK cells, but not of NA-NK cells. TRAM-34, however, does not affect their ability to form conjugates with target tumor cells, to migrate, or to express chemokine receptors. TRAM-34 and NS6180 also increase the proliferation of both A-NK and NA-NK cells. This results in a TRAM-34-induced increased ability of A-NK cells to reduce in vivo tumor growth. Taken together, our results suggest that targeting KCa3.1 on NK cells with selective blockers may be beneficial in cancer immunotherapy.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shyny
authors.initials: S
authors.lastname: Koshy
authors.forename: Danli
authors.initials: D
authors.lastname: Wu
authors.forename: Xueyou
authors.initials: X
authors.lastname: Hu
authors.forename: Rajeev B
authors.initials: RB
authors.lastname: Tajhya
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.forename: Fatima S
authors.initials: FS
authors.lastname: Khan
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Patricia
authors.initials: P
authors.lastname: Yotnda
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D000073718:Pancreatitis-Associated Proteins; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019409:Interleukin-15; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; D011720:Pyrazoles; C000612141:REG3A protein, human; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C411671:TRAM 34; D018664:Interleukin-12