Figure 2 Site of action of checkpoint inhibitors and agonists being

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Figure 2 Site of action of checkpoint inhibitors and agonists being tested in advanced renal cell carcinoma (RCC) Figure 2 | Site of action of checkpoint inhibitors and agonists being tested in advanced renal cell carcinoma (RCC). T-cell activation is regulated by various co-stimulatory and inhibitory checkpoints. Both agonistic antibodies to activating receptors and blocking antibodies to inhibitory receptors can stimulate T-cell activity and are being tested in advanced renal cell carcinoma and other solid tumours. Activation of T cells first requires an antigen-presenting cell (APC), such as a dendritic cell, to present an antigen. Here, an APC presents a tumour antigen complexed to major histocompatibility complex (MHC) class I to the T cell via the T cell receptor (TCR). Co-stimulatory signals are also needed at this time. At this point, B7 on an APC can bind to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) creating an inhibitory signal, but ipilimumab or tremelimumab — CTLA-4 antibodies — can inhibit the inhibitory signal by binding to CTLA-4 and promote T-cell activation. Once the activated T cell is in the tumour environment it can recognize the antigen presented by an APC cell in the tumour. At this time, the programmed cell death protein 1 (PD-1) receptor can also send an inhibitory signal to the T cell when the receptor binds to programmed cell death 1 ligand 1 (PD-L1), which is often expressed on tumour cells. Inhibition of PD-L1 or PD-1 could block that signal. Several PD-1 inhibitors are under investigation for RCC, including pembrolizumab and pidilizumab, and nivolumab was recently FDA approved for patients with RCC who have failed prior antiangiogenic therapy. PD-L1 inhibitors under investigation include atezolizumab, BMS-936559, durvalumab and avelumab. In addition to inhibitory receptors, several activating receptors exist that stimulate T-cell activity, including CD137, CD27, OX40 and GITR. Similarly, several agonist antibodies target these receptors are under investigation for RCC. These include urelumab targeting CD137, varlilumab targeting CD27, MEDI10562 targeting OX40, and MK-4166 and TRX518 targeting GITR. Carlo, M. I. et. al. (2016) Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma Nat. Rev. Urol. doi:10.1038/nrurol.2016.103