Molecular profiling of CD8 T cells from autochthonous melanoma identifies Maf as driver of T cell exhaustion (TUM2P.1004)

Abstract T-cells infiltrating neoplasms express surface molecules typical of chronically virus-stimulated T-cells, often termed “exhausted” T-cells. We analyzed the transcriptome of “exhausted” CD8 T-cells infiltrating autochthonous melanomas compared to those of naïve and acutely stimulated CD8 T-cells. In spite of strong similarities between transcriptional signatures of tumor- and virally-induced exhausted CD8 T-cells, notable differences appeared. Among transcriptional regulators, Nr4a2 was expressed in both exhaustions, whereas Maf was highly over-expressed only in tumor-exhausted T-cells. We confirmed Maf and nr4a2 up-regulation in Melan-A/MART-1 specific CD8 T cells from tumor infiltrated LN from melanoma patients. Anti-tumor CD8 T-cells transduced to express Maf showed dampened anti-tumor activity upon adoptive transfer, whereas Nr2a4 over-expression was without effect. Maf-expressing CD8 T-cells showed unaltered homeostasis but failed to accumulate in tumor-bearing hosts and developed defective anti-tumor secondary responses. We also found that Maf expression in CD8 T cells induced part of the transcriptional program associated with tumor-induced exhaustion. We further identified TGFβ as a main contributor to Maf expression in CD8 T-cells. Therefore the melanoma microenvironment contributes to skewing of CD8 T-cell differentiation programs, in part by TGFβ-mediated induction of Maf.