title: Molecular profiling of CD8 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 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.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Giordano
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Henin
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Maurizio
authors.affiliation: Clinical Tumor Biology & Immunotherapy Group, Department of Oncology and Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Imbratta
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bourdely
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Buferne
authors.affiliation: Clinical Tumor Biology & Immunotherapy Group, Department of Oncology and Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vanhille
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Sieweke
authors.affiliation: Clinical Tumor Biology & Immunotherapy Group, Department of Oncology and Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), UM2 Aix-Marseille Université, Marseille Cedex 9, France INSERM U1104, Marseille, France CNRS UMR7280, Marseille, France gregory.verdeil@unil.ch.
authors.forename: Grégory
authors.initials: G
authors.lastname: Verdeil
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D008156:Luciferases; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D015850:Interleukin-6; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein; D008156:Luciferases
keywords: Maf; TGFβ; T‐cell exhaustion; melanoma