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Background

Immune checkpoint inhibitors (ICPIs) have transformed the treatment of a range of cancers, including melanoma, non-small-cell lung carcinoma and transitional cell carcinoma. Understanding their mechanism of action at a molecular level allows us to better appreciate their clinical behaviour and to identify the next generation of immunotherapy agents.

The primary mediator of the immune response is the activated T cell, which expresses a multitude of different co-stimulatory and co-inhibitory factors, together making up the immune checkpoint (Table 2.1).1,2 The activated T cell, via the T cell receptor (TCR), is an effector of the adaptive immune response, leading to B cell responses, macrophage activation and cytotoxic cell killing.2

Table 2.1Checkpoints, ligands and therapeutic compounds (commercial and experimental) (adapted from Dempke et al.1 and Pardoll2).

It might be expected that tumour cells, with their diverse set of tumour-associated antigens acquired through genetic instability and epigenetic modification, would be easily recognized by the host immune system. Immune resistance through dysregulation of immune checkpoints is, however, commonplace, and leads to T cell exhaustion (Table 2.2) and, ultimately, deletion of tumour-specific T cells.2 Generally, the co-stimulatory pathways that regulate T cell activation are not implicated in tumour immune resistance. By contrast, the co-inhibitory pathways that negatively regulate T cell effector functions are often overexpressed in tumour cells.2

Table 2.2Role of co-inhibitory signals and cytokine production in T cell exhaustion. Upregulation of co-inhibitory pathways, with correlating patterns of cytokine production, leads to a stepwise loss of cytotoxic function and progression of the ‘exhausted’ phenotype. Severely exhausted T cells are eventually targeted for apoptosis and are therefore deleted from the host immune repertoire.13,7

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