Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy
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 11...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/14/3708 |
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| author | Maysa Vilbert Erica C. Koch April A. N. Rose Rob C. Laister Diana Gray Valentin Sotov Susanne Penny Anna Spreafico Devanand M. Pinto Marcus O. Butler Samuel D. Saibil |
| author_facet | Maysa Vilbert Erica C. Koch April A. N. Rose Rob C. Laister Diana Gray Valentin Sotov Susanne Penny Anna Spreafico Devanand M. Pinto Marcus O. Butler Samuel D. Saibil |
| author_sort | Maysa Vilbert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:12:34Z |
| format | Article |
| id | doaj.art-5629b1e6c96b4cab9263690d11aec22a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T01:12:34Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5629b1e6c96b4cab9263690d11aec22a2023-11-18T18:43:01ZengMDPI AGCancers2072-66942023-07-011514370810.3390/cancers15143708Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to ImmunotherapyMaysa Vilbert0Erica C. Koch1April A. N. Rose2Rob C. Laister3Diana Gray4Valentin Sotov5Susanne Penny6Anna Spreafico7Devanand M. Pinto8Marcus O. Butler9Samuel D. Saibil10Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaDepartment of Oncology, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, QC H3G 2M1, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaNational Research Council, Human Health Therapeutics, Halifax, NS B3H 3Y8, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaNational Research Council, Human Health Therapeutics, Halifax, NS B3H 3Y8, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, CanadaCutaneous 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.https://www.mdpi.com/2072-6694/15/14/3708melanomacutaneous melanomamucosal melanomauveal melanomaimmune-checkpoint inhibitorsmetabolomics |
| spellingShingle | Maysa Vilbert Erica C. Koch April A. N. Rose Rob C. Laister Diana Gray Valentin Sotov Susanne Penny Anna Spreafico Devanand M. Pinto Marcus O. Butler Samuel D. Saibil Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy Cancers melanoma cutaneous melanoma mucosal melanoma uveal melanoma immune-checkpoint inhibitors metabolomics |
| title | Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy |
| title_full | Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy |
| title_fullStr | Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy |
| title_full_unstemmed | Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy |
| title_short | Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy |
| title_sort | analysis of the circulating metabolome of patients with cutaneous mucosal and uveal melanoma reveals distinct metabolic profiles with implications for response to immunotherapy |
| topic | melanoma cutaneous melanoma mucosal melanoma uveal melanoma immune-checkpoint inhibitors metabolomics |
| url | https://www.mdpi.com/2072-6694/15/14/3708 |
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