Author(s): Sakthivel P, Gereke M, Bruder D
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Abstract Programmed Death-1 (PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2. The well-established immunosuppressive properties of PD-1/PD-L1 interaction resulting in the re-establishment of peripheral tolerance makes PD-1 an interesting target for therapeutic intervention in cancer patients. In addition to its relevance in tumor-specific immunity, recent studies demonstrate that PD-1 expression on T cells correlates with viral load in HIV and HCV infected patients and further identified PD-1 expression as a marker for exhausted virus-specific CD8+ T cells. In particular, PD-1+CD8+ T cells show impaired effector functions and PD-1 associated T cell exhaustion could be restored by blocking the PD-1/PD-L1 interaction. This results in recovery of virus-specific CD8+ T cell mediated immunity, suggesting that interrupting PD-1 signaling using an antagonistic antibody restores T-cell effector functions. Thus, immunotherapy based on the blockade of PD-1/PD-L1 interaction does not only result in breakdown of effector T-cell tolerance to tumor antigens, but in addition also represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections. In this review, we give a comprehensive overview about the immunological functions of PD-1 mediated signaling in T cells with special emphasis on its immune regulatory functions in the context of cancer and chronic viral infections. Moreover, we will summarize recent data obtained in animal models, in-vitro preclinical approaches in patients and their implementation in clinical trials for treating patients with cancer and chronic viral infections.
This article was published in Rev Recent Clin Trials
and referenced in Journal of Clinical & Cellular Immunology