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

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 TGFβ 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 TGFβ/IL-6-mediated induction of Maf.

Source: EMBO Journal - August 3, 2015 Category: Molecular Biology Authors: Giordano, M., Henin, C., Maurizio, J., Imbratta, C., Bourdely, P., Buferne, M., Baitsch, L., Vanhille, L., Sieweke, M. H., Speiser, D. E., Auphan-Anezin, N., Schmitt-Verhulst, A.-M., Verdeil, G. Tags: Immunology, Molecular Biology of Disease Articles Source Type: research