Role of ions channels in CAR-T cells

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dc.contributor.advisorHajdu Béla, Péter
dc.contributor.authorMedyouni, Ghofrane
dc.contributor.departmentMolekuláris orvostudomány doktori iskolahu
dc.contributor.submitterdepÁltalános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet
dc.contributor.submitterdepÁltalános Orvostudományi Kar::Biofizikai és Sejtbiológiai Intézet::Biofizikai Tanszék
dc.date.accessioned2025-10-13T18:17:41Z
dc.date.available2025-10-13T18:17:41Z
dc.date.defended2025-11-12
dc.date.issued2025
dc.description.abstractT cell ion channels (Kv1.3, KCa3.1 and CRAC) regulate the activation and effector functions via modulating the Ca2+-dependent pathway. Chimeric antigen receptor (CAR T cell therapy) showed a remarkable success in anti-tumor therapy, especially in the treatment of chemotherapy-resistant liquid cancers. Nevertheless, the mechanisms regulating CAR-T cell function as well as the side effects remain an area of active research.In our research study, we assessed the expression and role of ion channels in CAR T cells using a Jurkat-cell model and in primary T cells. Our results from molecular, electrophysiological and functional assays highlight that the KCa3.1 conductance in HER2-specific CAR T cells was higher compared to the non-transduced (NT, control) cells, which was more prominent in the CD8+ population (CD4+ cell also showed elevation). The Kv1.3 expression level was the same for all cell types (CD4+, CD8+, CAR, and NT). Single-cell Ca2+ imaging revealed that thapsigargin-induced SOCE via CRAC is suppressed in CD8+ CAR T cells, unlike for CD4+ and CD8+ NT cells. The use of specific antagonists (Kv1.3: Vm24; KCa3.1: TRAM-34): showed that the target cell elimination capacity of the CD8+ CAR T cells was improved either by blocking KCa3.1 or Kv1.3.By means of our Jurkat-CAR cell line we could show that Kv1.3 channels is colocalized with CAR and redistributes into the synapse between a CAR and a target cell. The biophysical properties of Kv1.3 channel are not vastly affected by the introduction of CAR in the cells when Kv1.3 is the only expressed channel. The blockage of Kv1.3 channel lateral movement to the synapse affects the killing potential of CAR-T cells, likely through disruption of the Ca2+-response upon IS formation. Overall, these data suggest that the manipulation of the Kv1.3 channel may contribute to the improvement of CAR-T immunotherapy and provide new insights for future clinical strategies.
dc.format.extent70
dc.identifier.urihttps://hdl.handle.net/2437/397909
dc.language.isoen
dc.subjection channel , CAR-T cells ,cancer
dc.subject.disciplineElméleti orvostudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleRole of ions channels in CAR-T cells
dc.title.translatedaz ioncsatorna sin CAR-T sejtek szerepe
dc.typePhD, doktori értekezéshu
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