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Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion

Item Type:Article
Title:Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
Creators Name:Giordano, M. and Henin, C. and Maurizio, J. and Imbratta, C. and Bourdely, P. and Buferne, M. and Baitsch, L. and Vanhille, L. and Sieweke, M.H. and Speiser, D.E. and Auphan-Anezin, N. and Schmitt-Verhulst, A.M. and Verdeil, G.
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 TGF{beta} 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 TGF{beta}/IL-6-mediated induction of Maf.
Keywords:Maf, Melanoma, T-Cell Exhaustion, TGF{beta}, Animals, Nice
Source:EMBO Journal
Publisher:EMBO Press / Wiley
Page Range:2042-2058
Date:4 August 2015
Official Publication:https://doi.org/10.15252/embj.201490786
PubMed:View item in PubMed

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