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Critical Reviews™ in Oncogenesis
Role for the cAMP-Protein Kinase A Signaling Pathway in Suppression of Antitumor Immune Responses by Regulatory T Cells
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo; and Department of Gastroenterological Surgery, Akershus University Hospital, N-1478 Lørenskog, Norway
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Norway
CD4+CD25+ regulatory T (Treg) cells are engaged in the maintenance of immunological self-tolerance and suppressive control of excessive immune responses to foreign antigens. Furthermore, Treg cells infiltrate tumor tissues and may impede immune surveillance against cancer and hamper the development of an effective antitumor immunity. Depletion of Treg cells in animal models has been demonstrated to provoke tumor immunity. Attenuation of Treg-mediated suppression is therefore an interesting strategy to enhance antitumor responses. We recently found that adaptive Treg cells express COX-2 and suppress responder T cells in a PGE2-cAMP-dependent manner, which can be reversed by COX-2 inhibitors or EP-receptor antagonists. The same mechanism also appeared to be operative in patients with colorectal cancer where treatment with COX-inhibitor or cAMP-antagonist enhanced antitumor immune responses to the same extent as depletion of Treg cells. This provides mechanism-based opportunities for pharmacological intervention to interfere with Treg immunosuppression. In this review we will discuss key mechanisms used by Treg cells to suppress antitumor immunity, with emphasis on the cAMP-PKA pathway. We will also highlight some of the roles of Treg cells in cancer.
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