title: Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth.
abstract: 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.
authors.affiliation: INSERM 866, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Hervieu
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bruchard
authors.forename: Pierre
authors.initials: P
authors.lastname: Vabres
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D003606:Dacarbazine; D007371:Interferon-gamma