Evaluation of S100A8/A9 and neutrophils as prognostic markers in metastatic melanoma patients under immune-checkpoint inhibition
•Increased levels of circulating S100A8/A9 during ICI and accumulation of TANs impair clinical outcome of metastatic melanoma.•These findings underline the relevance of neutrophils and S100A8/A9 as drivers of melanoma progression.•In clinical practice, serum S100A8/A9 and neutrophil counts could ser...
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| Veröffentlicht in: | Translational oncology 2025-02, Vol.52, p.102224, Article 102224 |
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| creator | Melzer, Yasmin F Fergen, Nadine L Mess, Christian Stadler, Julia-Christina Geidel, Glenn Schwietzer, Ysabel A Kött, Julian Pantel, Klaus Schneider, Stefan W Utikal, Jochen Wladykowski, Ewa Vidal-y-Sy, Sabine Bauer, Alexander T Gebhardt, Christoffer |
| description | •Increased levels of circulating S100A8/A9 during ICI and accumulation of TANs impair clinical outcome of metastatic melanoma.•These findings underline the relevance of neutrophils and S100A8/A9 as drivers of melanoma progression.•In clinical practice, serum S100A8/A9 and neutrophil counts could serve as follow-up markers during ICI.•Our study warrants for testing therapies targeting S100A8/A9 and other NET-associated factors in metastatic melanoma.
Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs.
These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and |
| doi_str_mv | 10.1016/j.tranon.2024.102224 |
| format | Article |
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Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs.
These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.
Graphical abstract. A) The aim of our study was to provide evidence for S100A8/A9 and neutrophils as valuable prognostic and predictive biomarkers for tumor growth in melanoma. Our research intention was to explore the link between circulating and tumor-resident factors. Identifying additional biomarkers could constitute the foundation for effective ICIs monitoring and novel combination therapies. B) Our study consisted of two parts: 1) We analyzed liquid biopsies and measured serum S100A8/A9 concentrations at two different time points via ELISA (MRP8/14) in a cohort of 43 stage III and IV melanoma patients treated with ICIs. We obtained neutrophil count in peripheral blood from routine clinical laboratory analysis. Using Kaplan Meier curves, we estimated the impact of increasing S100A8/A9 and neutrophil levels during therapy on PFS and OS. 2) We performed immunofluorescence staining of neutrophils with anti-CD15 and Alexa 594 on 292 tissue samples including melanocytic nevi, primary melanomas and metastases from 113 patients of different stages. The tissue punches were collected on tissue micro-arrays. We compared neutrophil accumulation in the three different tumor types and analyzed the impact of neutrophil infiltration on survival. [Display omitted]</description><identifier>ISSN: 1936-5233</identifier><identifier>DOI: 10.1016/j.tranon.2024.102224</identifier><identifier>PMID: 39700646</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Biomarker ; Immune-checkpoint inhibitors ; Inflammation ; Melanoma ; Neutrophils ; S100A8/A9 ; Tumor progression</subject><ispartof>Translational oncology, 2025-02, Vol.52, p.102224, Article 102224</ispartof><rights>2024</rights><rights>Copyright © 2024. Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c1566-509a25a650bfe6d6be4d3ee555e36402712dedec021b54374d0480353adbd68f3</cites><orcidid>0000-0002-4679-7137 ; 0000-0001-7090-9584 ; 0000-0003-2073-3909 ; 0009-0008-3999-5902 ; 0009-0007-4199-1807 ; 0000-0002-2288-6258 ; 0000-0001-8642-5226</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39700646$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Melzer, Yasmin F</creatorcontrib><creatorcontrib>Fergen, Nadine L</creatorcontrib><creatorcontrib>Mess, Christian</creatorcontrib><creatorcontrib>Stadler, Julia-Christina</creatorcontrib><creatorcontrib>Geidel, Glenn</creatorcontrib><creatorcontrib>Schwietzer, Ysabel A</creatorcontrib><creatorcontrib>Kött, Julian</creatorcontrib><creatorcontrib>Pantel, Klaus</creatorcontrib><creatorcontrib>Schneider, Stefan W</creatorcontrib><creatorcontrib>Utikal, Jochen</creatorcontrib><creatorcontrib>Wladykowski, Ewa</creatorcontrib><creatorcontrib>Vidal-y-Sy, Sabine</creatorcontrib><creatorcontrib>Bauer, Alexander T</creatorcontrib><creatorcontrib>Gebhardt, Christoffer</creatorcontrib><title>Evaluation of S100A8/A9 and neutrophils as prognostic markers in metastatic melanoma patients under immune-checkpoint inhibition</title><title>Translational oncology</title><addtitle>Transl Oncol</addtitle><description>•Increased levels of circulating S100A8/A9 during ICI and accumulation of TANs impair clinical outcome of metastatic melanoma.•These findings underline the relevance of neutrophils and S100A8/A9 as drivers of melanoma progression.•In clinical practice, serum S100A8/A9 and neutrophil counts could serve as follow-up markers during ICI.•Our study warrants for testing therapies targeting S100A8/A9 and other NET-associated factors in metastatic melanoma.
Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs.
These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.
Graphical abstract. A) The aim of our study was to provide evidence for S100A8/A9 and neutrophils as valuable prognostic and predictive biomarkers for tumor growth in melanoma. Our research intention was to explore the link between circulating and tumor-resident factors. Identifying additional biomarkers could constitute the foundation for effective ICIs monitoring and novel combination therapies. B) Our study consisted of two parts: 1) We analyzed liquid biopsies and measured serum S100A8/A9 concentrations at two different time points via ELISA (MRP8/14) in a cohort of 43 stage III and IV melanoma patients treated with ICIs. We obtained neutrophil count in peripheral blood from routine clinical laboratory analysis. Using Kaplan Meier curves, we estimated the impact of increasing S100A8/A9 and neutrophil levels during therapy on PFS and OS. 2) We performed immunofluorescence staining of neutrophils with anti-CD15 and Alexa 594 on 292 tissue samples including melanocytic nevi, primary melanomas and metastases from 113 patients of different stages. The tissue punches were collected on tissue micro-arrays. We compared neutrophil accumulation in the three different tumor types and analyzed the impact of neutrophil infiltration on survival. [Display omitted]</description><subject>Biomarker</subject><subject>Immune-checkpoint inhibitors</subject><subject>Inflammation</subject><subject>Melanoma</subject><subject>Neutrophils</subject><subject>S100A8/A9</subject><subject>Tumor progression</subject><issn>1936-5233</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNp9kEtv1DAUhb2gog_4Bwh52c3M-J1kU2lUtYBUiQWwthz7hvE0sVPbqcSOn46HtCxZWffqHJ97PoQ-ULKlhKrdcVuSCTFsGWGirhhj4g26oB1XG8k4P0eXOR8JUbRj7C06511TB6Eu0O-7ZzMupvgYcBzwN0rIvt3tO2yCwwGWkuJ88GPGJuM5xZ8h5uItnkx6hJSxD3iCYnIxf7cw1ismg-c6QigZL8FBwn6algAbewD7OEcfSvUdfO9Pqe_Q2WDGDO9f3iv04_7u--3nzcPXT19u9w8bS6WqLUhnmDRKkn4A5VQPwnEAKSVwJQhrKHPgwBJGeyl4IxwRLeGSG9c71Q78Cl2v_9YWTwvkoiefLYz1YohL1pyKRrS0bWSVilVqU8w5waDn5GvjX5oSfeKtj3rlrU-89cq72j6-JCz9BO6f6RV2FdysAqg9nz0knW3FZMH5BLZoF_3_E_4AEymWvQ</recordid><startdate>202502</startdate><enddate>202502</enddate><creator>Melzer, Yasmin F</creator><creator>Fergen, Nadine L</creator><creator>Mess, Christian</creator><creator>Stadler, Julia-Christina</creator><creator>Geidel, Glenn</creator><creator>Schwietzer, Ysabel A</creator><creator>Kött, Julian</creator><creator>Pantel, Klaus</creator><creator>Schneider, Stefan W</creator><creator>Utikal, Jochen</creator><creator>Wladykowski, Ewa</creator><creator>Vidal-y-Sy, Sabine</creator><creator>Bauer, Alexander T</creator><creator>Gebhardt, Christoffer</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4679-7137</orcidid><orcidid>https://orcid.org/0000-0001-7090-9584</orcidid><orcidid>https://orcid.org/0000-0003-2073-3909</orcidid><orcidid>https://orcid.org/0009-0008-3999-5902</orcidid><orcidid>https://orcid.org/0009-0007-4199-1807</orcidid><orcidid>https://orcid.org/0000-0002-2288-6258</orcidid><orcidid>https://orcid.org/0000-0001-8642-5226</orcidid></search><sort><creationdate>202502</creationdate><title>Evaluation of S100A8/A9 and neutrophils as prognostic markers in metastatic melanoma patients under immune-checkpoint inhibition</title><author>Melzer, Yasmin F ; Fergen, Nadine L ; Mess, Christian ; Stadler, Julia-Christina ; Geidel, Glenn ; Schwietzer, Ysabel A ; Kött, Julian ; Pantel, Klaus ; Schneider, Stefan W ; Utikal, Jochen ; Wladykowski, Ewa ; Vidal-y-Sy, Sabine ; Bauer, Alexander T ; Gebhardt, Christoffer</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1566-509a25a650bfe6d6be4d3ee555e36402712dedec021b54374d0480353adbd68f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Biomarker</topic><topic>Immune-checkpoint inhibitors</topic><topic>Inflammation</topic><topic>Melanoma</topic><topic>Neutrophils</topic><topic>S100A8/A9</topic><topic>Tumor progression</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Melzer, Yasmin F</creatorcontrib><creatorcontrib>Fergen, Nadine L</creatorcontrib><creatorcontrib>Mess, Christian</creatorcontrib><creatorcontrib>Stadler, Julia-Christina</creatorcontrib><creatorcontrib>Geidel, Glenn</creatorcontrib><creatorcontrib>Schwietzer, Ysabel A</creatorcontrib><creatorcontrib>Kött, Julian</creatorcontrib><creatorcontrib>Pantel, Klaus</creatorcontrib><creatorcontrib>Schneider, Stefan W</creatorcontrib><creatorcontrib>Utikal, Jochen</creatorcontrib><creatorcontrib>Wladykowski, Ewa</creatorcontrib><creatorcontrib>Vidal-y-Sy, Sabine</creatorcontrib><creatorcontrib>Bauer, Alexander T</creatorcontrib><creatorcontrib>Gebhardt, Christoffer</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Translational oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Melzer, Yasmin F</au><au>Fergen, Nadine L</au><au>Mess, Christian</au><au>Stadler, Julia-Christina</au><au>Geidel, Glenn</au><au>Schwietzer, Ysabel A</au><au>Kött, Julian</au><au>Pantel, Klaus</au><au>Schneider, Stefan W</au><au>Utikal, Jochen</au><au>Wladykowski, Ewa</au><au>Vidal-y-Sy, Sabine</au><au>Bauer, Alexander T</au><au>Gebhardt, Christoffer</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of S100A8/A9 and neutrophils as prognostic markers in metastatic melanoma patients under immune-checkpoint inhibition</atitle><jtitle>Translational oncology</jtitle><addtitle>Transl Oncol</addtitle><date>2025-02</date><risdate>2025</risdate><volume>52</volume><spage>102224</spage><pages>102224-</pages><artnum>102224</artnum><issn>1936-5233</issn><abstract>•Increased levels of circulating S100A8/A9 during ICI and accumulation of TANs impair clinical outcome of metastatic melanoma.•These findings underline the relevance of neutrophils and S100A8/A9 as drivers of melanoma progression.•In clinical practice, serum S100A8/A9 and neutrophil counts could serve as follow-up markers during ICI.•Our study warrants for testing therapies targeting S100A8/A9 and other NET-associated factors in metastatic melanoma.
Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs.
These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.
Graphical abstract. A) The aim of our study was to provide evidence for S100A8/A9 and neutrophils as valuable prognostic and predictive biomarkers for tumor growth in melanoma. Our research intention was to explore the link between circulating and tumor-resident factors. Identifying additional biomarkers could constitute the foundation for effective ICIs monitoring and novel combination therapies. B) Our study consisted of two parts: 1) We analyzed liquid biopsies and measured serum S100A8/A9 concentrations at two different time points via ELISA (MRP8/14) in a cohort of 43 stage III and IV melanoma patients treated with ICIs. We obtained neutrophil count in peripheral blood from routine clinical laboratory analysis. Using Kaplan Meier curves, we estimated the impact of increasing S100A8/A9 and neutrophil levels during therapy on PFS and OS. 2) We performed immunofluorescence staining of neutrophils with anti-CD15 and Alexa 594 on 292 tissue samples including melanocytic nevi, primary melanomas and metastases from 113 patients of different stages. The tissue punches were collected on tissue micro-arrays. We compared neutrophil accumulation in the three different tumor types and analyzed the impact of neutrophil infiltration on survival. [Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39700646</pmid><doi>10.1016/j.tranon.2024.102224</doi><orcidid>https://orcid.org/0000-0002-4679-7137</orcidid><orcidid>https://orcid.org/0000-0001-7090-9584</orcidid><orcidid>https://orcid.org/0000-0003-2073-3909</orcidid><orcidid>https://orcid.org/0009-0008-3999-5902</orcidid><orcidid>https://orcid.org/0009-0007-4199-1807</orcidid><orcidid>https://orcid.org/0000-0002-2288-6258</orcidid><orcidid>https://orcid.org/0000-0001-8642-5226</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biomarker Immune-checkpoint inhibitors Inflammation Melanoma Neutrophils S100A8/A9 Tumor progression |
| title | Evaluation of S100A8/A9 and neutrophils as prognostic markers in metastatic melanoma patients under immune-checkpoint inhibition |
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