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Molecular profiling of CD 8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
Author(s) -
Giordano Marilyn,
Henin Coralie,
Maurizio Julien,
Imbratta Claire,
Bourdely Pierre,
Buferne Michel,
Baitsch Lukas,
Vanhille Laurent,
Sieweke Michael H,
Speiser Daniel E,
AuphanAnezin Nathalie,
SchmittVerhulst AnneMarie,
Verdeil Grégory
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490786
Subject(s) - biology , cytotoxic t cell , cd8 , adoptive cell transfer , melanoma , cancer research , tumor microenvironment , transcriptome , interleukin 21 , transfection , microbiology and biotechnology , immunology , cell culture , in vitro , immune system , tumor cells , gene expression , genetics , gene
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” CD 8 T cells infiltrating autochthonous melanomas to those of naïve and acutely stimulated CD 8 T cells. Despite strong similarities between transcriptional signatures of tumor‐ and virus‐induced exhausted CD 8 T cells, notable differences appeared. Among transcriptional regulators, Nr4a2 and Maf were highly overexpressed in tumor‐exhausted T cells and significantly upregulated in CD 8 T cells from human melanoma metastases. Transduction of murine tumor‐specific CD 8 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 TGF β and IL ‐6 as main inducers of Maf expression in CD 8 T cells and showed that Maf ‐deleted tumor‐specific CD 8 T cells were much more potent to restrain tumor growth in vivo . Therefore, the melanoma microenvironment contributes to skewing of CD 8 T cell differentiation programs, in part by TGF β/ IL ‐6‐mediated induction of Maf .