Immune checkpoints and their inhibition in cancer and infectious diseases

The development of chronic infections and cancer is facilitated by a variety of immune subversion mechanisms, such as the production of anti-inflammatory cytokines, induction of regulatory T (Treg) cells and expression of immune checkpoint molecules, including CTLA-4 and PD-1. CTLA-4, expressed on T cells, interacts with CD80/CD86, thereby limiting T-cell activation and leading to anergy. PD-1 is predominantly expressed on T cells and its interaction with PD-L1 and PD-L2 expressed on antigen presenting cells (APCs) and tumours sends a negative signal to T cells, which can lead to T-cell exhaustion. Given their role in suppressing effector T-cell responses, immune checkpoints are being targeted for the treatment of cancer. Indeed, antibodies binding CTLA-4, PD-1 or PD-L1 have shown remarkable efficacy, especially in combination therapies, for a number of cancers and have been licensed for the treatment of melanoma, non-small cell lung cancer, renal and bladder cancers. Moreover, immune checkpoint inhibitors have been shown to enhance ex vivo effector T-cell responses from patients with chronic viral, bacterial or parasitic infection, including HIV, tuberculosis and malaria. Although the data from clinical trials in infectious diseases is still sparse, these inhibitors have great potential for treating chronic infections, especially when combined with therapeutic vaccines. This article is protected by copyright. All rights reserved.

European journal of immunology. 2017 Apr 09 [Epub ahead of print]

Lydia Dyck, Kingston H G Mills

Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

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