The blockade of immune checkpoints in cancer immunotherapy

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Abstract
The huge number of genetic and epigenetic changes that are inherent to most cancer cells provide plenty of tumour-associated antigens that the host immune system can recognize, thereby requiring tumours to develop specific immune resistance mechanisms. An important immune resistance mechanism involves immune-inhibitory pathways, termed immune checkpoints, which normally mediate immune tolerance and mitigate collateral tissue damage. A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates the amplitude of T cell activation. Antibody blockade of CTLA4 in mouse models of cancer induced antitumour immunity. Clinical studies using antagonistic CTLA4 antibodies demonstrated activity in melanoma. Despite a high frequency of immune-related toxicity, this therapy enhanced survival in two randomized Phase III trials. Anti-CTLA4 therapy was the first agent to demonstrate a survival benefit in patients with advanced melanoma and was approved by the US Food and Drug Administration (FDA) in 2010. Some immune-checkpoint receptors, such as programmed cell death protein 1 (PD1), limit T cell effector functions within tissues. By upregulating ligands for PD1, tumour cells block antitumour immune responses in the tumour microenvironment. Early-stage clinical trials suggest that blockade of the PD1 pathway induces sustained tumour regression in various tumour types. Responses to PD1 blockade may correlate with the expression of PD1 ligands by tumour cells. Multiple additional immune-checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumour cells, are prime targets for blockade, particularly in combination with approaches that enhance the activation of antitumour immune responses, such as vaccines.