TY - JOUR
T1 - Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
AU - Lesterhuis, W. Joost
AU - Punt, Cornelis J.A.
AU - Hato, Stanleyson V.
AU - Eleveld-Trancikova, Dagmar
AU - Jansen, Bastiaan J.H.
AU - Nierkens, Stefan
AU - Schreibelt, Gerty
AU - De Boer, Annemiek
AU - Van Herpen, Carla M.L.
AU - Kaanders, Johannes H.
AU - Van Krieken, Johan H.J.M.
AU - Adema, Gosse J.
AU - Figdor, Carl G.
AU - De Vries, I. Jolanda M.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79961016549&partnerID=8YFLogxK
U2 - 10.1172/JCI43656
DO - 10.1172/JCI43656
M3 - Article
C2 - 21765211
AN - SCOPUS:79961016549
SN - 0021-9738
VL - 121
SP - 3100
EP - 3108
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -