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STATing the importance of immune modulation by platinum chemotherapeutics.

Hato SV, de Vries IJ, Lesterhuis WJ - Oncoimmunology (2012)

Bottom Line: Platinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells.This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Immunology; Radboud University Medical Centre and Nijmegen Centre for Molecular Life Sciences; Nijmegen, The Netherlands.

ABSTRACT
Platinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells. This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Immune modulation by platinum chemotherapeutics. (A) Immunosuppressive tumor microenvironment. IL-4/IL-13 production by tumor cells and immune cells (not shown) leads to STAT6 phosphorylation in DCs and tumor cells. STAT6 phosphoylation leads to upregulation of PD-L2 expression resulting in immune evasion by induction of T cell tolerance and anergy. (B) Platinum treated tumor microenvironment. Platinum chemotherapeutics have a direct cytotoxic effect and inhibit STAT6 phosphorylation leading to a downregulation of PD-L2 expression. Decreased PD-L2 expression leads to increased activation and proliferation of T cells by DCs and enhanced recognition of tumor cells by T cells.
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Figure 1: Figure 1. Immune modulation by platinum chemotherapeutics. (A) Immunosuppressive tumor microenvironment. IL-4/IL-13 production by tumor cells and immune cells (not shown) leads to STAT6 phosphorylation in DCs and tumor cells. STAT6 phosphoylation leads to upregulation of PD-L2 expression resulting in immune evasion by induction of T cell tolerance and anergy. (B) Platinum treated tumor microenvironment. Platinum chemotherapeutics have a direct cytotoxic effect and inhibit STAT6 phosphorylation leading to a downregulation of PD-L2 expression. Decreased PD-L2 expression leads to increased activation and proliferation of T cells by DCs and enhanced recognition of tumor cells by T cells.

Mentions: PD-L1 and 2 are ligands of PD-1 on T cells and induce tolerance and anergy.5 PD-L2 expression is regulated by the IL-4/Signal transducer and activator of transcription 6 (STAT6) signaling pathway. Others have shown that IL-4 and IL-13 are abundantly present in the tumor microenvironment resulting in STAT6 activation.6 We found that platinum chemotherapeutics reversed the IL-4 induced phosphorylation of STAT6 in DCs as detected by westernblot. In accordance, siRNA mediated knockdown of STAT6 in DCs decreased the platinum-induced downregulation of PD-L2 and abolished the ability of platinum drugs to enhance T cell proliferation, showing that this effect is caused by inhibition of STAT6. These results show that platinum drugs can modulate immune responses by relieving inhibitory mechanisms (Fig. 1) and represent a novel immune-modulating function of platinum chemotherapeutics.


STATing the importance of immune modulation by platinum chemotherapeutics.

Hato SV, de Vries IJ, Lesterhuis WJ - Oncoimmunology (2012)

Figure 1. Immune modulation by platinum chemotherapeutics. (A) Immunosuppressive tumor microenvironment. IL-4/IL-13 production by tumor cells and immune cells (not shown) leads to STAT6 phosphorylation in DCs and tumor cells. STAT6 phosphoylation leads to upregulation of PD-L2 expression resulting in immune evasion by induction of T cell tolerance and anergy. (B) Platinum treated tumor microenvironment. Platinum chemotherapeutics have a direct cytotoxic effect and inhibit STAT6 phosphorylation leading to a downregulation of PD-L2 expression. Decreased PD-L2 expression leads to increased activation and proliferation of T cells by DCs and enhanced recognition of tumor cells by T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376994&req=5

Figure 1: Figure 1. Immune modulation by platinum chemotherapeutics. (A) Immunosuppressive tumor microenvironment. IL-4/IL-13 production by tumor cells and immune cells (not shown) leads to STAT6 phosphorylation in DCs and tumor cells. STAT6 phosphoylation leads to upregulation of PD-L2 expression resulting in immune evasion by induction of T cell tolerance and anergy. (B) Platinum treated tumor microenvironment. Platinum chemotherapeutics have a direct cytotoxic effect and inhibit STAT6 phosphorylation leading to a downregulation of PD-L2 expression. Decreased PD-L2 expression leads to increased activation and proliferation of T cells by DCs and enhanced recognition of tumor cells by T cells.
Mentions: PD-L1 and 2 are ligands of PD-1 on T cells and induce tolerance and anergy.5 PD-L2 expression is regulated by the IL-4/Signal transducer and activator of transcription 6 (STAT6) signaling pathway. Others have shown that IL-4 and IL-13 are abundantly present in the tumor microenvironment resulting in STAT6 activation.6 We found that platinum chemotherapeutics reversed the IL-4 induced phosphorylation of STAT6 in DCs as detected by westernblot. In accordance, siRNA mediated knockdown of STAT6 in DCs decreased the platinum-induced downregulation of PD-L2 and abolished the ability of platinum drugs to enhance T cell proliferation, showing that this effect is caused by inhibition of STAT6. These results show that platinum drugs can modulate immune responses by relieving inhibitory mechanisms (Fig. 1) and represent a novel immune-modulating function of platinum chemotherapeutics.

Bottom Line: Platinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells.This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Immunology; Radboud University Medical Centre and Nijmegen Centre for Molecular Life Sciences; Nijmegen, The Netherlands.

ABSTRACT
Platinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells. This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds.

No MeSH data available.


Related in: MedlinePlus