Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

Automated summary

Immune checkpoint inhibitors (ICIs) are effective cancer therapies but can cause immune-related adverse events (irAEs) with varying severity. The relationship between irAEs and antitumor immune responses is complex, depending on factors such as organ involvement, tumor histology, and individual patient characteristics. While some irAEs may indicate an immune response against tumor cells and healthy tissues, others may have no correlation with antitumor immunity. Low-grade irAEs appear to be positively associated with ICI treatment response, but the impact of severe irAEs on clinical benefit is unclear. Current management of severe irAEs involves interrupting or discontinuing ICI treatment and administering immunosuppressive agents, but this may compromise the anticancer effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have identified potential therapeutic targets for managing irAEs and preserving or enhancing ICI efficacy.