title: IFNγ producing CD8+T cells modified to resist major immune checkpoints induce regression of MHC class I-deficient melanomas.
abstract: Tumors with reduced expression of MHC class I (MHC-I) molecules may be unrecognized by tumor antigen-specific CD8+T cells and thus constitute a challenge for cancer immunotherapy. Here we monitored development of autochthonous melanomas in TiRP mice that develop tumors expressing a known tumor antigen as well as a red fluorescent protein (RFP) reporter knock in gene. The latter permits non-invasive monitoring of tumor growth by biofluorescence. One developing melanoma was deficient in cell surface expression of MHC-I, but MHC-I expression could be rescued by exposure of these cells to IFNγ. We show that CD8+T cells specific for tumor antigen/MHC-I were efficient at inducing regression of the MHC-I-deficient melanoma, provided that the T cells were endowed with properties permitting their migration into the tumor and their efficient production of IFNγ. This was the case for CD8+T cells transfected to express an active form of STAT5 (STAT5CA). The amount of IFNγ producedex vivofrom T cells present in tumors after adoptive transfer of the CD8+T cells was correlated with an increase in surface expression of MHC-I molecules by the tumor cells. We also show that these CD8+T cells expressed PD-1 and upregulated its ligand PDL-1 on melanoma cells within the tumor. Despite upregulation of this immunosuppressive pathway, efficient IFNγ production in the melanoma microenvironment was found associated with resistance of STAT5CA-expressing CD8+T cells to inhibition both by PD-1/PDL-1 engagement and by TGFβ1, two main immune regulatory mechanisms hampering the efficiency of immunotherapy in patients.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Michel
authors.initials: M
authors.lastname: Buferne
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Chasson
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Magali
authors.initials: M
authors.lastname: Grange
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Mas
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Arnoux
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bertuzzi
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Lee
authors.initials: L
authors.lastname: Leserman
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML); UM2 Aix-Marseille Université ; Marseille, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; 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, France ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Marseille; France ; Centre National de la Recherche Scientifique (CNRS) ; Marseille; France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
keywords: LN, lymph node; MFI, mean fluorescence intensity; STAT5, Signal transducer and activator of transcription 5; TA, tumor antigen; TILs, tumor infiltrating leukocytes; biofluorescence tumor imaging; cancer-germline tumor antigen; eTC, effector T cell; immunotherapy; mouse melanoma model; transcription factor; tumor escape variants