Seasonal patterns of toxicity in melanoma patients treated with combination anti-PD-1 and anti-CTLA-4 immunotherapy

Background: Immune checkpoint inhibitors are frequently associated with the development of immunotherapyrelated adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. Methods: We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. Results: 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season -specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season -specific patterns for early -onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early -onset pneumonitis was more frequent in autumn -winter (p = 0.008) and early -onset nephritis in spring -summer (p = 0.004). Conclusions: Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.