Mechanisms of checkpoint inhibition-induced adverse events

Abstract

Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non-small-cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self-tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune-related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field.

Keywords: CTLA-4; PD-1; cancer; checkpoint; immunotherapy.

Figure 1

The cytotoxic T lymphocyte antigen 4 (CTLA‐4) pathway is a target of immune checkpoint inhibitors. The CTLA‐4 pathway negatively regulates T cells in the early immune response. For initial T cell activation, two signals are required. Upon the delivery of signal 1 via T cell receptor–major histocompatibility complex (TCR–MHC) interaction, CTLA‐4 is up‐regulated on the cell surface, with peak expression at 48–72 h post‐TCR stimulation. Signal 2 of T cell activation is attained via interaction of CD28 with the co‐stimulatory molecules CD80 and CD86. As a CD28 homologue, CTLA‐4 also binds CD80 and CD86, but with a greater affinity than CD28. CTLA‐4 ligation with CD80/CD86 results in reduced CD28 binding, as well as negative downstream signalling through CTLA‐4, both of which result in inhibition T cell activation. This pathway has become a target of novel anti‐cancer therapies known as checkpoint inhibitors. Ipilimumab and tremelimumab are the two current CTLA‐4‐targeting monoclonal antibodies.

Figure 2

Downstream signalling of programmed cell death 1 (PD‐1) and cytotoxic T lymphocyte antigen 4 (CTLA‐4) is mediated by signalling phosphatases. Engagement of the T cell receptor (TCR) with major histocompatibility complex (MHC) begins a cascade of intracellular signalling resulting in T cell activation. The TCR cannot signal intracellularly itself; this is accomplished instead by the adjacent CD3 chains containing immunoreceptor tyrosine‐based activation motifs (ITAMs). Following TCR engagement, the ITAM motifs are phosphorylated by Fyn and Lck kinases, resulting in ZAP‐70 recruitment. ZAP‐70 is then phosphorylated by Fyn and Lck, activating it, and allowing the continuation of the downstream signalling. PD‐1/programmed cell death ligand 1 (PD‐L1) binding suppresses this pathway through the actions of the phosphatase Src homology region 2‐containing protein tyrosine phosphatase 2 (SHP‐2), which dephosphorylates ZAP‐70 and PI3K, inhibiting the signalling cascade. CTLA‐4 exerts its actions similarly through SHP‐2, but also through PP2A, which dephosphorylates AKT, further inhibiting the pathway.

Figure 3

The programmed cell death 1/programmed cell death ligand 1 (PD‐1/PD‐L1) pathway is utilized by tumours as immunosurveillance evasion strategy and is a target of immune checkpoint inhibitors. The PD‐1/PD‐L1 pathway supresses T cells in peripheral tissues and is involved at a later stage in the immune response than cytotoxic T lymphocyte antigen 4 (CTLA‐4). For initial T cell activation, two signals are required. Signal 1 is delivered in the form of T cell receptor–major histocompatibility complex (TCR–MHC) binding, while signal 2 is achieved through the engagement of co‐stimulatory molecules by CD28. After a T cell has been activated, the engagement of PD‐1 on the T cell with PD‐L1 on a tumour cell leads to T cell suppression, allowing tumours to avoid elimination by T cells. This pathway has become a target of novel anti‐cancer therapies known as checkpoint inhibitors. Nivolumab, pembrolizumab and cemiplimab are the three current PD‐1‐targeting monoclonal antibodies, while atezolizumab and avelumab are the two current PD‐L1‐targeting antibodies.

Figure 4

Immune checkpoint inhibitors have unique risk profiles. Drugs targeting different immune checkpoints have been found to trend towards specific immune‐related adverse effects (irAEs). The length of the bar corresponds to the relative incidence of these irAEs, while the colour is indicative of the pathway targeted. Increased proportions of red within the bar signifies toxicity more commonly associated with cytotoxic T lymphocyte antigen 4 (CTLA‐4) inhibitors, while blue represents toxicity more commonly associated with programmed cell death 1/programmed cell death ligand 1 (PD‐1/PD‐L1) inhibitors.