CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia.
Cell Rep
; 37(9): 110079, 2021 11 30.
Article
em En
| MEDLINE
| ID: mdl-34852226
ABSTRACT
CD19-CAR T cell therapy has evolved into the standard of care for relapsed/refractory B cell acute lymphoblastic leukemia (ALL); however, limited persistence of the CAR T cells enables tumor relapse for many patients. To gain a deeper understanding of the molecular characteristics associated with CAR T cell differentiation, we performed longitudinal genome-wide DNA methylation profiling of CD8+ CD19-CAR T cells post-infusion in ALL patients. We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes. The CAR T cell post-infusion changes are further characterized by repression of genes (e.g., TCF7 and LEF1) associated with memory potential and a DNA methylation signature (e.g., demethylation at CX3CR1, BATF, and TOX) demarcating a transition toward exhaustion-progenitor T cells. Thus, CD19-CAR T cells undergo exhaustion-associated DNA methylation programming, indicating that efforts to prevent this process may be an attractive approach to improve CAR T cell efficacy.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Receptores de Antígenos de Linfócitos T
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Regulação Neoplásica da Expressão Gênica
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Imunoterapia Adotiva
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Linfócitos T CD8-Positivos
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Antígenos CD19
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Metilação de DNA
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Leucemia-Linfoma Linfoblástico de Células Precursoras
Limite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2021
Tipo de documento:
Article