Journal
CANCER RESEARCH
Volume 73, Issue 18, Pages 5647-5656Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-12-3788
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Funding
- German Research Foundation (DFG German Research Foundation) initiative CRC [52/A7, STE791/6-1, 1066/B6]
- initiative CRC [1066/B8]
- German Cancer Aid [110631]
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IFN-alpha is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune-and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-alpha remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-alpha deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-alpha-mediated Treg inactivation increased CD4_ effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-alpha-induced MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphodiesterase 4 (PDE4) activation and accompanied by downregulation of IFN receptor (IFNAR)-2 and negative regulation of T-cell receptor signaling. IFN-alpha did not affect the anergic state, cytokine production, Foxp3 expression, or methylation state of the Treg-specific demethylated region (TSDR) within the FOXP3 locus associated with a stable imprinted phenotype of human Treg. Abrogated protection by IFN-alpha-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-alpha-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-alpha activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-alpha treatment in patients with cancer and suggests IFN-alpha for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens. (C) 2013 AACR.
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