Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.

Keywords: B cell; CTLA-4; PD-1; PD-L1; T cell; arthritis; autoantibodies; autoreactivity; checkpoint; co-stimulation.

Fig. 1

Two-step signalling process for activation of naïve T cells Antigen presenting cells (APCs) such as dendritic cells (DCs) or B cells present antigen to T cells via MHC class I or II molecules (signal 1). The co-stimulatory signal occurs with binding of CD80/86 on an APC (A) to the CD28 receptor on the CD25⁺CD4⁺ T cell resulting in upregulation of immune responses (signal 2). Alternatively, a co-inhibitory signal can occur with binding of the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) receptor on the CD25⁺CD4⁺ T cell to CD80/86 (B) or binding of PD-1 on the peripheral T cell to PD-L1 or PD-L2 on an APC (B); both pathways result in downregulation of immune responses. Tumour cells can evade immune system recognition via upregulation of PD-L1 or PD-L2 on the tumour cell surface (C) to bind with CD8⁺ T cells resulting in downregulation of immune response. DC: dendritic cell; MHC: major histocompatibility complex.