Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice

作者：W. Joost Lesterhuis, Cornelis J.A. Punt, Stanleyson V. Hato, Dagmar Eleveld-Trancikova, Bas Jansen, Stefan Nierkens, Gerty Schreibelt, Annemiek de Boer, Carla M.L. van Herpen, Johannes H.A.M. Kaanders, J. Han van Krieken, Gosse J. Adema, Carl G. Figdor, I. Jolanda M. de Vries · 发表于：Journal of Clinical Investigation · 年份：2011 · DOI：10.1172/jci43656 · 被引用次数：348 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction、Immune cells in cancer

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...