Molecular profiling of CD 8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion

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 antitumor effector responses. We further identified TGFb 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 TGFb/IL-6-mediated induction of Maf.

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

“…All comparison populations and statistics used to generate gene sets have been published (17, 31-34). For gene sets corresponding to human data, gene symbols were converted to mouse gene symbols by the Database for Annotation, Visualization and Integrated Discovery (DAVID) version 6.7 (35, 36), and gene symbols were manually verified to contain the gene symbol identifier(s) corresponding to our microarray Probe Set ID’s.…”

Molecular Dissection of CD8 + T-Cell Dysfunction

“…The loss of CD4 + T cell help, particularly in the form of IL-21 [4–6] and signaling downstream of the immunosuppressive cytokines, IL-10 and TGF-β, were shown to promote T cell dysfunction [7, 8]. More recently, IL-6 signaling, alone or in combination with TGF-β, was shown to induce the transcription factor Maf, a potential driver of CD8 + T cell dysfunction in tumor [9]; however the role of IL-6 in driving dysfunctional phenotype in vivo was not addressed. That Maf is driven by Stat3 signaling [10] further raises the possibility that other cytokines that activate Stat3 may also play a role in regulating T cell dysfunction.…”

“…Several gene signatures (see glossary) based on analyses of populations of dysfunctional CD8 + T cells from cancer and chronic viral infections have been published [9, 21–25]. These signatures have shown that there is great similarity between virus- and cancer-associated CD8 + T cell dysfunction and have greatly advanced our understanding of factors that contribute to dysfunctional phenotype.…”

“…The leucine zipper-containing transcription factor Maf was reported to be up-regulated in dysfunctional CD8 + TILs in murine melanoma tumors and in TILs from melanoma patients when compared to naïve and effector CD8 + T cells [9]. Loss of Maf resulted in better tumor control while overexpression resulted in dampened TIL accumulation and anti-tumor activity.…”

MAFdrives CD8+T-cell exhaustion

“…In our recent study, 3 we took advantage of a mouse model of induced melanoma based on conditional deletion of tumor suppressor genes with concomitant expression of a natural mouse tumor antigen (TiRP mice). In this model, tumorintrinsic factors control the development of aggressive tumors and their expression of an inflammatory/immunosuppressive program.…”