Overexpression of PDE4A Acts as Checkpoint Inhibitor Against cAMP-Mediated Immunosuppression in vitro

• Published in: Frontiers in immunology Vol. 10; p. 1790
• Main Authors: Schmetterer, Klaus G, Goldhahn, Katrin, Ziegler, Liesa S, Gerner, Marlene C, Schmidt, Ralf L J, Themanns, Madeleine, Zebedin-Brandl, Eva, Trapin, Doris, Leitner, Judith, Pickl, Winfried F, Steinberger, Peter, Schwarzinger, Ilse, Marculescu, Rodrig
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30.07.2019
• Subjects: adoptive immunotherapy; CD8-Positive T-Lymphocytes - immunology; checkpoint inhibitor; Cyclic AMP - genetics; Cyclic AMP - immunology; Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4 - immunology; Dinoprostone - genetics; Dinoprostone - immunology; Gene Expression Regulation, Enzymologic - immunology; HEK293 Cells; Humans; Immune Tolerance; Immunology; T-cell engineering; T-Lymphocytes, Regulatory - immunology; tumor immunosuppression; immune tolerance; tumor immunosuppression; adoptive immunotherapy; T-cell engineering; checkpoint inhibitor
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.01790

Malignant cells acquire physiological mechanisms of immunosuppression to escape immune surveillance. Strategies to counteract this suppression could help to improve adoptive immunotherapy regimen. The intracellular second messenger cyclic AMP (cAMP) acts as a potent immunosuppressive signaling molecule in T-cells and is up-regulated by multiple tumor-relevant suppressive factors including prostaglandin E2 (PGE2), adenosine and the functions of regulatory T-cells. Consequently, we aimed to abrogate cAMP signaling in human T-cells by ectopic overexpression of phosphodiesterase 4A (PDE4A). We could show that retroviral transduction of PDE4A into T-cells led to efficient degradation of cAMP in response to induction of adenylate cyclase. Retroviral transduction of PDE4A into CD4 and CD8 T-cells restored proliferation, cytokine secretion as well as cytotoxicity under immunosuppression by PGE2 and A2A-R agonists. PDE4A-transgenic T-cells were also partially protected from suppression by regulatory T-cells. Furthermore, PGE2-mediated upregulation of the inhibitory surface markers CD73 and CD94 on CD8 T-cells was efficiently counteracted by PDE4A. Importantly, no differences in the functionality under non-suppressive conditions between PDE4A- and control-vector transduced T-cells were observed, indicating that PDE4A does not interfere with T-cell activation . Similarly, expression of surface markers associated with T-cell exhaustion were not influenced by PDE4A overexpression in long term cultures. Thus, we provide first evidence that PDE4A can be exploited as immune checkpoint inhibitor against multiple suppressive factors.