title: Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice.
abstract: Tumor microenvironments feature immune inhibitory mechanisms that prevent T cells from generating effective antitumor immune responses. Therapeutic interventions aimed at disrupting these inhibitory mechanisms have been shown to enhance antitumor immunity, but they lack direct cytotoxic effects. Here, we investigated the effect of cytotoxic cancer chemotherapeutics on immune inhibitory pathways. We observed that exposure to platinum-based chemotherapeutics markedly reduced expression of the T cell inhibitory molecule programmed death receptor-ligand 2 (PD-L2) on both human DCs and human tumor cells. Downregulation of PD-L2 resulted in enhanced antigen-specific proliferation and Th1 cytokine secretion as well as enhanced recognition of tumor cells by T cells. Further analysis revealed that STAT6 controlled downregulation of PD-L2. Consistent with these data, patients with STAT6-expressing head and neck cancer displayed enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared with patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation. We therefore conclude that platinum-based anticancer drugs can enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capability of tumor cells. This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds.
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands. w.lesterhuis@onco.umcn.nl
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Stanleyson V
authors.initials: SV
authors.lastname: Hato
authors.forename: Dagmar
authors.initials: D
authors.lastname: Eleveld-Trancikova
authors.forename: Bastiaan J H
authors.initials: BJ
authors.lastname: Jansen
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Gerty
authors.initials: G
authors.lastname: Schreibelt
authors.forename: Annemiek
authors.initials: A
authors.lastname: de Boer
authors.forename: Carla M L
authors.initials: CM
authors.lastname: Van Herpen
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Kaanders
authors.forename: Johan H J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology; D018572:Disease-Free Survival; D015536:Down-Regulation; D006801:Humans; D007107:Immune System; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D002945:Cisplatin