Mechanisms Driving Immune-Related Adverse Events in Cancer Patients Treated with Immune Checkpoint Inhibitors

In the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer treatment. With the continuing rise in the number of cancer patients eligible for ICIs, a corresponding rise in immune-related adverse events (irAEs) is occurring. IrAEs are inflammatory reactions against normal, healthy tissue that occur due to ICI-induced activation of the immune system. Although the exact immune pathogenesis driving irAE development remains unknown, we review the main proposed mechanisms, highlighting how they may inform irAE prediction and treatment.

IrAEs are common and diverse, varying in incidence, timing, and severity. The possible mechanisms driving irAEs include (1) activation of cytotoxic T cells; (2) activation of B cells and increased autoantibody production; (3) direct molecular mimicry and off-target toxicity; (4) activation of intracellular signaling and pro-inflammatory cytokine production; and (5) environmental modifiers of immune system activation, including composition of the host gut microbiome. These mechanisms may help identify predictive biomarkers and targeted treatment strategies. IrAEs are driven by multiple components of the immune system. More research is needed to understand their immunopathogenesis so that clinicians across all specialties may more effectively monitor and manage these increasingly common conditions.