Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion.
EMBO J
; 34(15): 2042-58, 2015 Aug 04.
Article
en En
| MEDLINE
| ID: mdl-26139534
ABSTRACT
T cells infiltrating neoplasms express surface molecules typical of chronically virus-stimulated T cells, often termed "exhausted" T cells. We compared the transcriptome of "exhausted" CD8 T cells infiltrating autochthonous melanomas to those of naïve and acutely stimulated CD8 T cells. Despite strong similarities between transcriptional signatures of tumor- and virus-induced exhausted CD8 T cells, notable differences appeared. Among transcriptional regulators, Nr4a2 and Maf were highly overexpressed in tumor-exhausted T cells and significantly upregulated in CD8 T cells from human melanoma metastases. Transduction of murine tumor-specific CD8 T cells to express Maf partially reproduced the transcriptional program associated with tumor-induced exhaustion. Upon adoptive transfer, the transduced cells showed normal homeostasis but failed to accumulate in tumor-bearing hosts and developed defective anti-tumor effector responses. We further identified TGFß and IL-6 as main inducers of Maf expression in CD8 T cells and showed that Maf-deleted tumor-specific CD8 T cells were much more potent to restrain tumor growth in vivo. Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGFß/IL-6-mediated induction of Maf.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Diferenciación Celular
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Linfocitos T CD8-positivos
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Proteínas Proto-Oncogénicas c-maf
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Microambiente Tumoral
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Melanoma
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2015
Tipo del documento:
Article