Molecular profiling of CD 8 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”CD8T cells infiltrating autochthonous melanomas to those of naive and acutely stimulated CD8T cells. Despite strong similarities between transcriptional signatures of tumor- and virus-induced exhausted CD8T cells, notable differences appeared. Among transcriptional regulators,Nr4a2andMafwere highly overexpressed in tumor-exhausted T cells and significantly upregulated in CD8T cells from human melanoma metastases. Transduction of murine tumor-specific CD8 T cells to expressMafpartially 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 antitumor effector responses. We further identified TGFband IL-6as main inducers ofMafexpression in CD8T cells and showed that Maf-deleted tumor-specific CD8T cells were much more potent to restrain tumor growthin vivo.Therefore, the melanoma microenvironment contributes to skewing of CD8T cell differentiation programs, in part by TGFb/IL-6-mediated induction ofMaf.