6533b836fe1ef96bd12a0b09
RESEARCH PRODUCT
Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth.
Grégoire MignotAlice HervieuCédric RébéLionel ApetohFrédérique VégranFanny ChalminFrançois GhiringhelliMélanie BruchardPierre Vabressubject
Skin NeoplasmsMelanoma ExperimentalCD8-Positive T-LymphocytesPharmacologyMESH: Antineoplastic Agents AlkylatingLigandsBiochemistryMiceInterleukin 210302 clinical medicineMESH: Up-RegulationMESH: LigandsCytotoxic T cell[ SDV.IMM ] Life Sciences [q-bio]/ImmunologyMESH: AnimalsMESH : Up-RegulationMESH : LigandsMESH : Melanoma ExperimentalMelanomaMESH : Mice NudeMESH : CD8-Positive T-LymphocytesMESH: CD8-Positive T-LymphocytesUp-Regulation3. Good healthDacarbazineKiller Cells NaturalMESH: Melanoma ExperimentalNK Cell Lectin-Like Receptor Subfamily K030220 oncology & carcinogenesisMESH: NK Cell Lectin-Like Receptor Subfamily K[SDV.IMM]Life Sciences [q-bio]/ImmunologyMESH : Killer Cells Naturalmedicine.drugMESH: Killer Cells NaturalMESH: Cell Line Tumor[SDV.IMM] Life Sciences [q-bio]/ImmunologyMESH: Interferon-gammaDacarbazineMESH : Antineoplastic Agents AlkylatingMice NudeMESH : Mice Inbred C57BLDermatologyBiologyMajor histocompatibility complexMESH: DacarbazineInterferon-gamma03 medical and health sciencesImmune systemDownregulation and upregulationMESH: Mice Inbred C57BLCell Line TumorMESH : MicemedicineMESH : NK Cell Lectin-Like Receptor Subfamily KMESH: Mice NudeAnimalsHumansMESH : DacarbazineAntineoplastic Agents AlkylatingMolecular BiologyMESH: MiceMESH : Interferon-gammaMESH: HumansMESH : Cell Line TumorMESH: Skin NeoplasmsMESH : Skin NeoplasmsMESH : HumansCell Biologymedicine.diseaseMESH : Disease Models AnimalMice Inbred C57BLDisease Models Animalbiology.proteinMESH : AnimalsMESH: Disease Models AnimalCD8030215 immunologydescription
International audience; Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-02-01 |