Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Maysa Vilbert
ORCID logo ,
Erica C. Koch
,
April A.N. Rose
,
Rob C. Laister
,
Diana Gray
,
Valentin Sotov
,
Susanne Penny
,
Anna Spreafico
ORCID logo ,
David Hogg
,
Devanand M. Pinto
,
Marcus O. Butler
ORCID logo ,
Samuel D. Saibil
*
Version 1 : Received: 29 May 2023 / Approved: 31 May 2023 / Online: 31 May 2023 (10:45:46 CEST)

A peer-reviewed article of this Preprint also exists.

Vilbert, M.; Koch, E.C.; Rose, A.A.N.; Laister, R.C.; Gray, D.; Sotov, V.; Penny, S.; Spreafico, A.; Pinto, D.M.; Butler, M.O.; Saibil, S.D. Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy. Cancers 2023, 15, 3708. Vilbert, M.; Koch, E.C.; Rose, A.A.N.; Laister, R.C.; Gray, D.; Sotov, V.; Penny, S.; Spreafico, A.; Pinto, D.M.; Butler, M.O.; Saibil, S.D. Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy. Cancers 2023, 15, 3708.

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 patients with lower SPM levels. Our study revealed 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.

Keywords

melanoma; cutaneous melanoma; mucosal melanoma; uveal melanoma; immune-checkpoint inhibitors; metabolomics; tryptophan; kynurenine; spermine

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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