Tumor miRNA expression as a potential biomarker of immune-related toxicity in patients with melanoma or urothelial carcinoma treated with immune checkpoint inhibitors.

Abstract

e14588 Background: Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in several solid tumors, including melanoma and urothelial carcinoma. However, their clinical benefit is often limited by the development of immune-related adverse events (irAEs), which can compromise treatment continuation and patient quality of life. Identifying molecular biomarkers capable of predicting immune-related toxicity remains an unmet clinical need in oncology. MicroRNAs (miRNAs), small non-coding RNAs involved in immune regulation and tumor biology, have emerged as promising biomarkers, due to their potential role in predicting ICI- related toxicity. Methods: We investigated the association between tumor tissue miRNA expression and the development of irAEs in patients with melanoma (n = 69) or urothelial carcinoma (n = 108) treated with ICI agents. MiRNAs were extracted from formalin-fixed paraffin-embedded tumor biopsies, and their expression were analyzed by quantitative PCR. Nineteen miRNAs were selected based on evidence from publicly available studies addressing implication in immune response and signaling pathways potentially associated with the development of irAEs after ICI treatment. Results: In this study, miRNA expression levels were not associated with sociodemographic characteristics or type of ICI in either cohort. In the melanoma cohort, 55.1% of patients developed irAEs. Lower tumor expression of miR-125b-5p (p = 0.05), miR-182-5p (p = 0.031), miR-192-5p (p = 0.031), and miR-199a-5p (0.035) were significantly associated with the occurrence of global irAEs. Similarly, reduced expression of these miRNAs was observed in patients who developed fatigue/asthenia, the most common irAE, occurring in 36.8% of melanoma patients with irAEs. Furthermore, distinct miRNAs expression patterns were associated with specific irAE, including arthritis, hepatitis, and thyroiditis. In the urothelial carcinoma cohort, no miRNAs were associated with global irAEs. However, lower tumor expression of miR-34c-5p was significantly associated with ICI-induced pneumonitis (p = 0.037) and miR-493-5p expression with ICI-induced asthenia (p = 0.027). Conclusions: Tumor miRNAs expression were associated with global irAEs in patients with melanoma treated with ICIs, whereas such associations were not observed for overall toxicity in urothelial carcinoma. Exploratory associations were found between specific miRNAs expression and individual irAEs in both cohort of patients suggesting the potential role of miRNAs as biomarkers of irAEs. Further studies will be required to validate these preliminary results. Key words: Immune checkpoint inhibitors (ICIs), Immune-related adverse events (irAEs), Melanoma, Urothelial carcinoma, tumor miRNAs expression.