Contribution of the Skin–Gut Axis to Immune-Related Adverse Events with Multi-System Involvement

SIMPLE SUMMARY: Increasing numbers of cancer patients are treated with immunotherapy that activates their immune systems to control or even eliminate tumors. However, a substantial proportion of patients experience adverse events mediated by the unleashed immune system. The skin is one of the most frequently affected organs, with toxicities typically manifesting as distinct types of rashes. The gastrointestinal (GI) tract is also commonly affected, with a wide spectrum of symptom manifestations that can range from self-limited diarrhea to life-threatening colitis. Here we present the relationship between skin and GI adverse events among cancer patients receiving treatment with immune checkpoint blockade, which has not been well-studied. ABSTRACT: Immune-related adverse events (irAEs) frequently complicate treatment with immune checkpoint blockade (ICB) targeting CTLA-4, PD-1, and PD-L1, which are commonly used to treat solid and hematologic malignancies. The skin and gastrointestinal (GI) tract are most frequently affected by irAEs. While extensive efforts to further characterize organ-specific adverse events have contributed to the understanding and management of individual toxicities, investigations into the relationship between multi-organ toxicities have been limited. Therefore, we aimed to conduct a characterization of irAEs occurring in both the skin and gut. A retrospective analysis of two cohorts of patients treated with ICB at Memorial Sloan Kettering Cancer Center was conducted, including a cohort of patients with cutaneous irAEs (ircAEs) confirmed by dermatologists (n = 152) and a cohort of patients with biopsy-proven immune-related colitis (n = 246). Among both cohorts, 15% (61/398) of patients developed both skin and GI irAEs, of which 72% (44/61) patients had ircAEs preceding GI irAEs (p = 0.00013). Our study suggests that in the subset of patients who develop both ircAEs and GI irAEs, ircAEs are likely to occur first. Further prospective studies with larger sample sizes are needed to validate our findings, to assess the overall incidence of co-incident irAEs, and to determine whether ircAEs are predictors of other irAEs. This analysis highlights the development of multi-system dermatologic and gastrointestinal irAEs and underscores the importance of oncologists, gastroenterologists, and dermatologists confronted with an ircAE to remain alert for additional irAEs.