Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
W. Joost Lesterhuis, … , Carl G. Figdor, I. Jolanda M. de Vries
W. Joost Lesterhuis, … , Carl G. Figdor, I. Jolanda M. de Vries
Published July 18, 2011
Citation Information: J Clin Invest. 2011;121(8):3100-3108. https://doi.org/10.1172/JCI43656.
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Research Article Oncology

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

W. Joost Lesterhuis, Cornelis J.A. Punt, Stanleyson V. Hato, Dagmar Eleveld-Trancikova, Bastiaan J.H. Jansen, Stefan Nierkens, Gerty Schreibelt, Annemiek de Boer, Carla M.L. Van Herpen, Johannes H. Kaanders, Johan H.J.M. van Krieken, Gosse J. Adema, Carl G. Figdor, I. Jolanda M. de Vries

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Figure 2

Enhanced T cell stimulatory potential of DCs matured with cytokines or TLR ligands in the presence of platinum chemotherapy in an antigen-specific model.

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Enhanced T cell stimulatory potential of DCs matured with cytokines or T...
(A) KLH-specific T cells were cocultured with KLH-loaded DCs, matured with cytokines or R848 and poly(I:C), in the presence or absence of platinum chemotherapy. cDC, cytokine-matured DCs; TLR-DC, TLR ligand–matured DCs; Ox, oxaliplatin. A representative experiment is shown. n = 3. (B) Enhanced IFN-γ secretion by T cells in MLR upon exposure to TLR ligand–matured DCs cultured with platinum as compared with platinum-untreated DCs. A representative experiment is shown. n = 3. *P < 0.05; **P < 0.01; ***P < 0.001. Data are depicted as mean + SEM.