Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy

SIMPLE SUMMARY: Advanced melanoma is an aggressive cancer with a historical 12-month median survival after the diagnosis. This scenario has greatly changed since the advent of immunotherapy. Unfortunately, half of patients do not respond to this treatment and rare types of melanomas such as mucosal and uveal are known for their poorer outcomes compared to cutaneous melanoma. We investigated the serum metabolome of patients with these three melanomas subtypes, aiming to identify metabolic profiles that correlate with response to immunotherapy. Our results indicate that mucosal and uveal melanomas have a very distinct profile of circulating metabolites compared to cutaneous melanomas, mainly in the kynurenine pathway. Uveal melanoma, the most resistant subtype, also exhibits higher levels of sphingolipids and spermine. The later was associated with a poor survival in patients treated with immunotherapy. These results contribute to the growing evidence about tumoral resistance mechanisms to immunotherapy, with potential implication for future targeted therapies. ABSTRACT: Cutaneous melanoma (CM) patients respond better to immune checkpoint inhibitors (ICI) than mucosal and uveal melanoma patients (MM/UM). Aiming to explore these differences and understand the distinct response to ICI, we evaluated the serum metabolome of advanced CM, MM, and UM patients. Levels of 115 metabolites were analyzed in samples collected before ICI, using a targeted metabolomics platform. In our analysis, molecules involved in the tryptophan-kynurenine axis distinguished UM/MM from CM. UM/MM patients had higher levels of 3-hydroxykynurenine (3-HKyn), whilst patients with CM were found to have higher levels of kynurenic acid (KA). The KA/3-HKyn ratio was significantly higher in CM versus the other subtypes. UM, the most ICI-resistant subtype, was also associated with higher levels of sphingomyelin-d18:1/22:1 and the polyamine spermine (SPM). Overall survival was prolonged in a cohort of CM patients with lower SPM levels, suggesting there are also conserved metabolic factors promoting ICI resistance across melanoma subtypes. Our study revealed a distinct metabolomic profile between the most resistant melanoma subtypes, UM and MM, compared to CM. Alterations within the kynurenine pathway, polyamine metabolism, and sphingolipid metabolic pathway may contribute to the poor response to ICI. Understanding the different metabolomic profiles introduces opportunities for novel therapies with potential synergic activity to ICI, to improve responses of UM/MM.