4.7 Article

Innate T-αβ lymphocytes as new immunological components of anti-tumoral off-target effects of the tyrosine kinase inhibitor dasatinib

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SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-60195-z

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资金

  1. INSERM
  2. CHU de Poitiers
  3. Universite de Poitiers
  4. Ligue contre le Cancer du Grand Ouest (Comites departementaux de la Vienne, de la Charente, de la Charente Maritime et des Deux-Sevres)
  5. Association pour la Recherche en Immunologie-Poitou-Charentes (ARIM-PC)
  6. Canceropole Grand Sud-Ouest
  7. Groupement Interregional de Recherche Clinique et d'Innovation Sud-Ouest Outre-Mer (API-K 2017)
  8. Association Laurette Fugain [ALF 2015/10, ALF 2019/10]
  9. Fondation Brystol-Meyers Squibb
  10. Region Nouvelle Aquitaine
  11. Sport & Collection fellowship
  12. [INCa-DGOS 8658 (PRT-K 2015-052)]

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Kinase inhibitors hold great potential as targeted therapy against malignant cells. Among them, the tyrosine kinase inhibitor dasatinib is known for a number of clinically relevant off-target actions, attributed in part to effects on components of the immune system, especially conventional T-cells and natural killer (NK)-cells. Here, we have hypothesized that dasatinib also influences non-conventional T-alpha beta cell subsets known for their potential anti-tumoral properties, namely iNKT cells and the distinct new innate CD8 T-cell subset. In mice, where the two subsets were originally characterized, an activated state of iNKT cells associated with a shift toward an iNKT cell Th1-phenotype was observed after dasatinib treatment in vivo. Despite decreased frequency of the total memory CD8 T-cell compartment, the proportion of innate-memory CD8 T-cells and their IFN gamma expression in response to an innate-like stimulation increased in response to dasatinib. Lastly, in patients administered with dasatinib for the treatment of BCR-ABL-positive leukemias, we provided the proof of concept that the kinase inhibitor also influences the two innate T-cell subsets in humans, as attested by their increased frequency in the peripheral blood. These data highlight the potential immunostimulatory capacity of dasatinib on innate T-alpha beta cells, thereby opening new opportunities for chemoimmunotherapy.

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