Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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 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.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 2042-58 |
Seitenumfang | 17 |
Fachzeitschrift | The EMBO journal |
Jahrgang | 34 |
Ausgabenummer | 15 |
Publikationsstatus | Veröffentlicht - 4 Aug. 2015 |
Peer-Review-Status | Ja |
Extern publiziert | Ja |
Externe IDs
PubMedCentral | PMC4551351 |
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Scopus | 84938739934 |
Schlagworte
Schlagwörter
- Animals, CD8-Positive T-Lymphocytes/cytology, Cell Differentiation/immunology, DNA Primers/genetics, Flow Cytometry, Gene Expression Profiling, Homeodomain Proteins/genetics, Interleukin-6/metabolism, Luciferases, Melanoma/metabolism, Mice, Mice, Transgenic, Proto-Oncogene Proteins c-maf/genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Transforming Growth Factor beta/metabolism, Tumor Microenvironment/physiology