Immune checkpoint inhibitors in renal cell carcinoma

Abstract

The immune system has long been known to play a critical role in the body's defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes.

Keywords: cancer; immunology; immunomodulation.

Figure 1. Immune checkpoints and immune checkpoint inhibitors in RCC

Recognition of tumour cells and APCs via MHC–antigen interactions with TCRs activates T cells. IFN-γ released from T cells results in up-regulation of PD-L1 expression. PD-1 is expressed on activated T cells and on interaction with PD-L1 on tumour cells or APCs results in inhibition of T cell antitumour response. CTLA-4 is expressed on T cells and on interaction with its ligands CD80/CD86 on APCs, T-cell proliferation and T-cell effector function is reduced. CD28 is a co-stimulatory T-cell molecule, which has a lower affinity than CTLA-4 for their shared ligands; CD80/CD86. Blockade of PD-1, PD-L1 and CTLA-4 with mAbs stimulates an enhanced antitumour response and has shown efficacy in aRCC. Abbreviations: aRCC, advanced renal cell cancer; APC, antigen presenting cell; CD28, cluster of differentiation 28; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; CTLA-4, cytotoxic T lymphocyte associated protein 4; IFN-γ, interferon-γ; IFN-γR, interferon-γ receptor; mAb, monoclonal antibody; PD-1, programmed death-1; PD-L1, programmed death ligand 1; TCR, T-cell receptor.