American Association for Cancer Research
00085472can123788-sup-can-12-3788_figures_and_figure_legends.pdf (251.19 kB)

Supplementary Figures and Figure Legends from Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

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journal contribution
posted on 2023-03-30, 21:52 authored by Nicole Bacher, Verena Raker, Claudia Hofmann, Edith Graulich, Melanie Schwenk, Ria Baumgrass, Tobias Bopp, Ulrich Zechner, Luzie Merten, Christian Becker, Kerstin Steinbrink

PDF file, 251K, Supplemental Figure 1. CD56+CD16+ NK cells isolation from buffy coats. Suppelmental Figure 2. IFN-alpha treatment impairs STAT1 activation in Treg. Supplemental Figure 3. IFN-alpha did not affect Foxp3 expression in Treg. Supplemental Figure 4. Pharmacological repression of cAMP production in Treg does not affect ZAP-70 phosphorylation.



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+CD25highFoxp+ 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. Cancer Res; 73(18); 5647–56. ©2013 AACR.

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