CTLA-4 – two pathways to anti-tumour immunity?

Abstract Immune checkpoint inhibitor (ICI) therapies have revolutionised cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1 and LAG-3. Despite their success, efficacy and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICI affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is direct enhancement of effector T cell responses through simple blockade of CTLA-4 - “releasing the brakes”, while the second requires prior elimination of regulatory T cells (TREG) to allow emergence of T cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.