Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-09, Vol.73 (18), p.5647-5656
• Main Authors: BACHER, Nicole, RAKER, Verena, STEINBRINK, Kerstin, HOFMANN, Claudia, GRAULICH, Edith, SCHWENK, Melanie, BAUMGRASS, Ria, BOPP, Tobias, ZECHNER, Ulrich, MERTEN, Luzie, BECKER, Christian
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Autoimmunity - drug effects; Biological and medical sciences; Cells, Cultured; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - metabolism; DNA-Binding Proteins - physiology; Extracellular Signal-Regulated MAP Kinases - metabolism; Graft vs Host Disease - immunology; Graft vs Host Disease - metabolism; Graft vs Host Disease - pathology; Humans; Interferon-alpha - pharmacology; Interleukin-2 Receptor alpha Subunit - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Lymphocyte Activation; Medical sciences; Mice; Mitogen-Activated Protein Kinase Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation; STAT Transcription Factors - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3788

IFN-α 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-α remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-α deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-α-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-α-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-α 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-α-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-α-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-α activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-α treatment in patients with cancer and suggests IFN-α for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens.