| Autor: |
Vilbert M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada., Koch EC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile., Rose AAN; Department of Oncology, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, QC H3G 2M1, Canada., Laister RC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada., Gray D; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada., Sotov V; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada., Penny S; National Research Council, Human Health Therapeutics, Halifax, NS B3H 3Y8, Canada., Spreafico A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada., Pinto DM; National Research Council, Human Health Therapeutics, Halifax, NS B3H 3Y8, Canada., Butler MO; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada., Saibil SD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.; Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada. |
| Abstrakt: |
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. |
