Abstract
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 per se. Similarly, expression of surface markers associated with T-cell exhaustion were not influenced by PDE4A overexpression in long term cultures. Thus, we provide first in vitro evidence that PDE4A can be exploited as immune checkpoint inhibitor against multiple suppressive factors.
Highlights
One of the cardinal features of malignant processes is their ability to suppress anti-tumor immune responses, which allows them to escape the physiological tumor-immunosurveillance [1]
In line with previous reports [46], we found that treatment of Jurkat T-cells with these inhibitors partially restored IL2 promoter activity upon activation in the presence of suppressive concentrations of prostaglandin E2 (PGE2) (Figure 1A)
But a significant increase in IL-2 promoter activity was found at highly suppressive concentrations (1,000 nM PGE2; n = 4; p < 0.01 for Rp-8-Br-cAMPS and p < 0.05 for H89 compared to mock-treated cells)
Summary
One of the cardinal features of malignant processes is their ability to suppress anti-tumor immune responses, which allows them to escape the physiological tumor-immunosurveillance [1]. Most strategies to enhance the efficacy of T-cell therapy have aimed to improve tumor recognition by ectopic expression of tumor-antigen specific TCR or chimeric antigen receptors (CAR) In this respect, both approaches have shown great promise in various malignancies and recently first therapeutic applications of CAR T-cells have been approved by the FDA for the treatment of advanced ALL and B-NHL [7, 8] and have been recommended by the EMA. It can be envisioned that T-cells can be equipped with antigen-receptors as well as internal checkpoint inhibitors to guarantee optimal anti-tumor immunity In this context, the definition of crucial immunoregulatory mechanisms, as well as measures to overcome their functions, should bear high therapeutic relevance
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