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 1

DCs exposed to platinum-based chemotherapy display enhanced allogeneic T cell stimulatory capacity.

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DCs exposed to platinum-based chemotherapy display enhanced allogeneic T...
(A) DCs were cultured in clinically relevant concentrations of chemotherapeutics during 48 hours of cytokine maturation and subsequently used in a mixed lymphocyte reaction with allogeneic PBMCs. T cell proliferation was measured by 3H-thymidine incorporation after 5 days. Ctrl, control DCs (nontreated); MTX, methotrexate; Cyta, cytarabine; Vinc, vincristine; Irino, irinotecan; Eto, etoposide; Bleo, bleomycin; DTIC, dacarbazine; Gem, gemcitabine; 5-FU, 5-fluorouracil; Doxo, doxorubicin; Lena, lenalidomide; Carb, carboplatin. For all proliferation experiments, the statistical analyses were performed against the control unless otherwise specified in the figure; the mean of 6 replicates per experiment and the SEM are depicted. A representative experiment is shown. n = 3. **P < 0.01; ***P < 0.001. (B) Same experiment with different platinum-based chemotherapeutics. Oxali, oxaliplatin; cis, cisplatin. A representative experiment is shown. n = 3. (C) Concentration-dependent effect of platinum exposure on T cell stimulatory potential of DCs. This effect was observed irrespective of whether the platinum drugs were added during or after DC maturation (data not shown). Oxaliplatin concentrations 0.5, 2.0, 3.0, and 4.0 μg/ml. A representative experiment is shown. n = 5. (D and E) IFN-γ and IL-2 secretion by T cells in MLR upon exposure to DCs cultured with or without platinum. A representative experiment is shown. n = 3. In the IL-2 experiment, the P value was 0.07, but the difference may be important in a microenvironment of marked T cell proliferation and hence increased IL-2 consumption. Data are depicted as mean + SEM.