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Las células T CD8 similares a las células madre median la respuesta de la inmunoterapia con células adoptivas contra

Sri Krishna¹, Frank J Lowery¹, Amy R Copeland¹

¹Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Science (New York, N.Y.)

|December 11, 2020

Resumen

La terapia con células T adoptivas (ACT) es prometedora para la regresión del cáncer. Los investigadores identificaron fenotipos específicos de linfocitos infiltrados en el tumor (TIL) vinculados a resultados exitosos de ACT, distinguiendo entre TILs similares al tallo y terminalmente diferenciados.

Área de la Ciencia:

Inmunología
En el campo de la oncología
Biología celular

Sus antecedentes:

La terapia con células T adoptivas (ACT) que utiliza linfocitos autólogos que se infiltran en el tumor (TIL) puede inducir la regresión completa del cáncer.
Los fenotipos específicos de TILs que se correlacionan con el éxito clínico en ACT siguen siendo en gran medida indefinidos.
La comprensión de los fenotipos TIL es crucial para optimizar la eficacia de ACT.

Objetivo del estudio:

Investigar el impacto de los fenotipos de TIL en el éxito clínico de TIL-ACT.
Identificar subconjuntos específicos de TIL asociados con la regresión completa del cáncer y la persistencia a largo plazo.
Caracterizar las capacidades funcionales de diferentes fenotipos de TIL en respuesta a los neoantígenos antitumorales.

Principales métodos:

Análisis de alta dimensión de los productos de ACT para humanos.
Caracterización fenotípica de las TIL utilizando marcadores como CD39 y CD69.
Evaluación de las capacidades de persistencia, auto-renovación y expansión de TIL.
Evaluación de las respuestas antitumorales in vivo.

Principales resultados:

Un fenotipo progenitor de memoria parecido a un tallo (CD39 negativo, CD69 negativo) se asoció con la regresión completa del cáncer y la persistencia de TIL.
Un fenotipo terminalmente diferenciado (CD39 positivo, CD69 positivo) correlacionado con una baja persistencia de TIL.
Mientras que la mayoría de las TIL reactivas a los neoantígenos se diferenciaron terminalmente, los que respondieron al ACT mantuvieron un grupo de TILs similares al tallo y específicos para el neoantígeno.
Las TILs reactivas al tumor demostraron una auto-renovación superior, expansión, persistencia y actividad antitumoral in vivo.

Conclusiones:

Los subconjuntos de TIL que median la respuesta ACT son distintos de los enriquecidos para la reactividad antitumoral inmediata.
La presencia de TILs neoantígenos similares al tallo es crítica para los efectos terapéuticos sostenidos en ACT.
La orientación o el enriquecimiento para estas poblaciones de TIL similares al tallo pueden mejorar la eficacia de ACT para el tratamiento del cáncer.

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