Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy
Abstract Background Immune checkpoint inhibitors (ICIs), such as anti-Cytotoxic T-Lymphocyte Antigen 4(CTLA-4) and anti-Programmed cell death protein 1 (PD-1) agents, have improved the prognosis of patients with metastatic melanoma. However, a proportion of patients develop resistance to these treat...
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BMC
2025-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03378-8 |
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| author | Susan Costantini Gabriele Madonna Mariaelena Capone Elena Di Gennaro Palmina Bagnara Federica Renza Domenico Mallardo Roberta Affatato Carlo Vitagliano Marilena Romanelli Marilena Tuffanelli Ester Simeone Gennaro Ciliberto Paolo A. Ascierto Alfredo Budillon |
| author_facet | Susan Costantini Gabriele Madonna Mariaelena Capone Elena Di Gennaro Palmina Bagnara Federica Renza Domenico Mallardo Roberta Affatato Carlo Vitagliano Marilena Romanelli Marilena Tuffanelli Ester Simeone Gennaro Ciliberto Paolo A. Ascierto Alfredo Budillon |
| author_sort | Susan Costantini |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs), such as anti-Cytotoxic T-Lymphocyte Antigen 4(CTLA-4) and anti-Programmed cell death protein 1 (PD-1) agents, have improved the prognosis of patients with metastatic melanoma. However, a proportion of patients develop resistance to these treatments, leading to a poor prognosis. Therefore, identifying potential non invasive and easy to measure biomarkers is crucial for guiding treatment strategies in patients with metastatic melanoma. Methods A retrospective single-center study was conducted involving patients with metastatic stage IV melanoma who received first-line treatment with anti-CTL4 and/or anti-PD-1 agents. The patients were categorized into two groups on the basis of their 1-year overall survival (OS): those with good outcomes (long-term OS ≥ 1 year) and those with poor outcomes (short-term OS < 1 year). Peripheral metabolomics was performed using baseline sera from 132 patients via 600 MHz Nuclear Magnetic Resonance (NMR) spectroscopy. Enriched functional analysis was conducted to identify the metabolic pathways in which significant metabolites were involved. Results Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing the metabolomics profiles of samples collected before ICI treatment revealed significantly different levels of metabolites between the two groups (long-term OS vs. short-term OS). Specifically, lactate, tryptophan and valine significantly predicted the OS of the whole study population subjected to ICI immunotherapy; alanine, asparagine, glutathione, histidine, isoleucine and phenylalanine significantly predicted the OS of patients treated with ipilimumab; glucose, glutamine, histidine and proline significantly predicted the OS of patients treated with nivolumab; and lactate, lysine and proline significantly predicted the OS of patients treated with ipilimumab plus nivolumab. Notably, tryptophan levels were correlated with treatment response in the overall patient group, whereas histidine and lactate levels were associated with response in patients treated with ipilimumab and with ipilimumab plus nivolumab, respectively. Interestingly, higher pretreatment levels of histidine were commonly found in long-term OS subgroups of patients treated with ipilimumab, nivolumab or ipilimumab plus nivolumab. Interestingly, considering only those metabolites that predict OS after univariate analysis, higher histidine, and lower lactate and proline levels resulted as associated with favorable OS in at least two patient cohorts. Conclusions Overall, this exploratory liquid biopsy study revealed a strong correlation between the pretreatment levels of some metabolites and the OS of patients with metastatic stage IV melanoma treated with anti-CTL4 and/or anti-PD-1 antibodies in the first-line setting and revealed the potential of these molecules to predict outcomes and define personalized management and treatment strategies. |
| format | Article |
| id | doaj-art-c67f28f7116246c7a668d652ad0d9b5f |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-c67f28f7116246c7a668d652ad0d9b5f2025-08-20T02:17:13ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-04-0144112010.1186/s13046-025-03378-8Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapySusan Costantini0Gabriele Madonna1Mariaelena Capone2Elena Di Gennaro3Palmina Bagnara4Federica Renza5Domenico Mallardo6Roberta Affatato7Carlo Vitagliano8Marilena Romanelli9Marilena Tuffanelli10Ester Simeone11Gennaro Ciliberto12Paolo A. Ascierto13Alfredo Budillon14Experimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleExperimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleExperimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleExperimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleExperimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleExperimental Pharmacology Unit, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleIRCCS National Cancer Istituto Regina ElenaCancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleScientific Directorate, Istituto Nazionale Tumori—IRCCS—Fondazione G. PascaleAbstract Background Immune checkpoint inhibitors (ICIs), such as anti-Cytotoxic T-Lymphocyte Antigen 4(CTLA-4) and anti-Programmed cell death protein 1 (PD-1) agents, have improved the prognosis of patients with metastatic melanoma. However, a proportion of patients develop resistance to these treatments, leading to a poor prognosis. Therefore, identifying potential non invasive and easy to measure biomarkers is crucial for guiding treatment strategies in patients with metastatic melanoma. Methods A retrospective single-center study was conducted involving patients with metastatic stage IV melanoma who received first-line treatment with anti-CTL4 and/or anti-PD-1 agents. The patients were categorized into two groups on the basis of their 1-year overall survival (OS): those with good outcomes (long-term OS ≥ 1 year) and those with poor outcomes (short-term OS < 1 year). Peripheral metabolomics was performed using baseline sera from 132 patients via 600 MHz Nuclear Magnetic Resonance (NMR) spectroscopy. Enriched functional analysis was conducted to identify the metabolic pathways in which significant metabolites were involved. Results Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing the metabolomics profiles of samples collected before ICI treatment revealed significantly different levels of metabolites between the two groups (long-term OS vs. short-term OS). Specifically, lactate, tryptophan and valine significantly predicted the OS of the whole study population subjected to ICI immunotherapy; alanine, asparagine, glutathione, histidine, isoleucine and phenylalanine significantly predicted the OS of patients treated with ipilimumab; glucose, glutamine, histidine and proline significantly predicted the OS of patients treated with nivolumab; and lactate, lysine and proline significantly predicted the OS of patients treated with ipilimumab plus nivolumab. Notably, tryptophan levels were correlated with treatment response in the overall patient group, whereas histidine and lactate levels were associated with response in patients treated with ipilimumab and with ipilimumab plus nivolumab, respectively. Interestingly, higher pretreatment levels of histidine were commonly found in long-term OS subgroups of patients treated with ipilimumab, nivolumab or ipilimumab plus nivolumab. Interestingly, considering only those metabolites that predict OS after univariate analysis, higher histidine, and lower lactate and proline levels resulted as associated with favorable OS in at least two patient cohorts. Conclusions Overall, this exploratory liquid biopsy study revealed a strong correlation between the pretreatment levels of some metabolites and the OS of patients with metastatic stage IV melanoma treated with anti-CTL4 and/or anti-PD-1 antibodies in the first-line setting and revealed the potential of these molecules to predict outcomes and define personalized management and treatment strategies.https://doi.org/10.1186/s13046-025-03378-8MelanomaMetabolomicsSerum biomarkersImmune checkpoint inhibitors |
| spellingShingle | Susan Costantini Gabriele Madonna Mariaelena Capone Elena Di Gennaro Palmina Bagnara Federica Renza Domenico Mallardo Roberta Affatato Carlo Vitagliano Marilena Romanelli Marilena Tuffanelli Ester Simeone Gennaro Ciliberto Paolo A. Ascierto Alfredo Budillon Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy Journal of Experimental & Clinical Cancer Research Melanoma Metabolomics Serum biomarkers Immune checkpoint inhibitors |
| title | Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| title_full | Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| title_fullStr | Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| title_full_unstemmed | Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| title_short | Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| title_sort | metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy |
| topic | Melanoma Metabolomics Serum biomarkers Immune checkpoint inhibitors |
| url | https://doi.org/10.1186/s13046-025-03378-8 |
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