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.