{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:39:43Z","timestamp":1790843983730,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (IT-MOH)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori\u2014IRCCS\u2014Fondazione \u201cG. Pascale\u201d, Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient\u2019s response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan\u2013Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003\u20130.213; p &lt; 0.0001. Gene: HR = 0.053, 95% CI: 0.011\u20130.260; p &lt; 0.0001). The Kaplan\u2013Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071\u20130.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05\u20130.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2\u20133), with a significant difference vs. the low-risk group (median PFS = not reached; p &lt; 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5\u20139) compared to patients with high expression of protein and gene signatures (median OS = not reached; p &lt; 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.<\/jats:p>","DOI":"10.3390\/ijms25179345","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T11:54:10Z","timestamp":1724846050000},"page":"9345","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A Combined Proteomic and Transcriptomic Signature Is Predictive of Response to Anti-PD-1 Treatment: A Retrospective Study in Metastatic Melanoma Patients"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-5313","authenticated-orcid":false,"given":"Domenico","family":"Mallardo","sequence":"first","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0790-892X","authenticated-orcid":false,"given":"Mario","family":"Fordellone","sequence":"additional","affiliation":[{"name":"Mental and Physical Health and Preventive Medicine, Medical Statistics Unit, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"White","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Vowinckel","sequence":"additional","affiliation":[{"name":"Biognosys AG, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bailey","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sparano","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Mallardo","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Arianna","family":"Facchini","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7899-3071","authenticated-orcid":false,"given":"Rosaria","family":"De Filippi","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, Universit\u00e0 degli Studi di Napoli Federico II, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cytopathology, Istituto Nazionale Tumori IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Vanella","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Beeler","sequence":"additional","affiliation":[{"name":"Biognosys AG, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-2264","authenticated-orcid":false,"given":"Paolo","family":"Chiodini","sequence":"additional","affiliation":[{"name":"Mental and Physical Health and Preventive Medicine, Medical Statistics Unit, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Cesano","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Warren","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo A.","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori\u2014IRCCS Fondazione \u201cG. Pascale\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","article-title":"KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-year survival with combined nivolumab and ipilimumab in advanced melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N. Engl. J. 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