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Las células CAR T senolíticas revierten las patologías asociadas a la senescencia

Corina Amor1,2, Judith Feucht3,4, Josef Leibold2

  • 1Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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|June 20, 2020
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Resumen

Las células T del receptor del antígeno quimérico (CAR) dirigidas al receptor del activador del plasminógeno tipo urokinasa (uPAR) eliminan eficazmente las células senescentes. Este enfoque senolítico muestra potencial terapéutico para enfermedades relacionadas con la edad y mejora la supervivencia en modelos preclínicos.

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Área de la Ciencia:

  • Biología celular
  • La inmunoterapia
  • Investigación sobre el envejecimiento

Sus antecedentes:

  • La senescencia celular, un estado de parada del ciclo celular estable, juega un doble papel en la supresión del tumor y la curación de heridas.
  • La acumulación anormal de células senescentes conduce a la inflamación crónica y contribuye a enfermedades relacionadas con la edad como la fibrosis y la osteoartritis.
  • La eliminación de células senescentes (senólisis) ha demostrado ser prometedora para mejorar los síntomas de la enfermedad y prolongar la vida útil en estudios preclínicos.

Objetivo del estudio:

  • Investigar el potencial terapéutico de las células T receptoras de antígenos quiméricos (CAR) como agentes senolíticos.
  • Identificar un objetivo específico en las células senescentes para la eliminación mediada por células CAR T.
  • Evaluar la eficacia de las células T CAR específicas de uPAR en modelos preclínicos de enfermedades asociadas a la senescencia.

Principales métodos:

  • Identificación de marcadores de la superficie celular inducidos ampliamente en células senescentes.
  • Desarrollo y caracterización de las células T CAR específicas del receptor activador del plasminógeno tipo urokinasa (uPAR).
  • Pruebas in vitro e in vivo de las células T CAR específicas de uPAR para la actividad senolítica en modelos de adenocarcinoma pulmonar y fibrosis hepática.

Principales resultados:

  • uPAR fue identificado como una proteína de la superficie celular inducida ampliamente durante la senescencia celular.
  • Las células T CAR específicas de uPAR demostraron una ablación eficiente de las células senescentes in vitro e in vivo.
  • La terapia con células T CAR dirigida a uPAR prolongó la supervivencia en ratones con adenocarcinoma pulmonar inducido por fármacos y restauró la homeostasis tisular en modelos de fibrosis hepática.

Conclusiones:

  • uPAR es un objetivo terapéutico viable para las células senescentes.
  • Las células CAR T senolíticas dirigidas a uPAR representan una estrategia terapéutica prometedora para las enfermedades asociadas a la senescencia.
  • Este enfoque tiene potencial para el tratamiento de enfermedades que van desde complicaciones del cáncer hasta enfermedades fibróticas crónicas.