Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
Open Access
- 1 August 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (8), 3100-3108
- https://doi.org/10.1172/jci43656
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.Keywords
This publication has 38 references indexed in Scilit:
- 5-Fluorouracil Selectively Kills Tumor-Associated Myeloid-Derived Suppressor Cells Resulting in Enhanced T Cell–Dependent Antitumor ImmunityCancer Research, 2010
- Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in miceJCI Insight, 2010
- Anticancer immunochemotherapy using adjuvants with direct cytotoxic effectsJCI Insight, 2009
- PD-1 and Its Ligands in Tolerance and ImmunityAnnual Review of Immunology, 2008
- Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapyNature Medicine, 2007
- Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor developmentThe Journal of Experimental Medicine, 2007
- Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Regulation of T cell activation and tolerance by PDL2Proceedings of the National Academy of Sciences of the United States of America, 2006
- No evidence for dualism in function and receptors: PD‐L2/B7‐DC is an inhibitory regulator of human T cell activationEuropean Journal of Immunology, 2006
- The STATs of cancer — new molecular targets come of ageNature Reviews Cancer, 2004