Tumour cells have the uncanny ability to evade the immune response, and a range of approaches are being developed to boost anticancer responses of T cells and restore their ability to detect and attack cancer cells. One of these approaches is immune-checkpoint targeting—the inhibition of receptors that would normally dampen the immune response. This principle has recently been clinically validated by ipilimumab, an inhibitory monoclonal antibody (mAb) that was approved for the treatment of advanced melanoma in 2011 and targets the immune checkpoint receptor cytotoxic T lymphocyte antigen 4 (CTLA4). Now, two reports in the New England Journal of Medicine describe early-stage clinical trials of two mAbs that target signalling through another immune checkpoint protein—the T cell co-inhibitory receptor programmed cell death protein 1 (PD1).

PD1 has a similar structure to CTLA4, but a distinct biological function and specificity. CTLA4 regulates T cells at the stage of initial activation, whereas PD1 dampens the immune response of activated T cells. In contrast to CTLA4 ligands, the PD1 ligands PDL1 and PDL2 are predominantly expressed within the tumour microenvironment, where they mediate the inhibition of T cells during long-term antigen exposure. It is thought that tumour cells induce these inhibitory receptors in response to an immune attack, a mechanism that has been termed adaptive resistance.