{"doi":"10.3389/fimmu.2023.1171978","title":"Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum are prognostic of melanoma patient outcomes","abstract":"Background Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics. Methods Levels of TLS-kines in patients’ sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed. Results Serum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL13 and CXCL10 tumor transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high APRIL/CXCL10/CXCL13 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Conclusion Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.","journal":"Frontiers in Immunology","year":2023,"id":359528,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9674,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1110137,"name":"Hassan Abushukair","orcid":"0000-0002-0068-5201","position":1,"is_corresponding":false},{"id":1053596,"name":"Aofei Li","orcid":null,"position":2,"is_corresponding":false},{"id":49252,"name":"Andrew Knight","orcid":"0000-0002-9753-6199","position":3,"is_corresponding":false},{"id":1110471,"name":"Ayah Nedal Al Bzour","orcid":null,"position":4,"is_corresponding":false},{"id":1110138,"name":"Ian MacFawn","orcid":"0000-0001-9056-1255","position":5,"is_corresponding":false},{"id":403073,"name":"Zachary Thompson","orcid":"0009-0006-5654-8915","position":6,"is_corresponding":false},{"id":728366,"name":"Ann Chen","orcid":"0000-0002-5377-3125","position":7,"is_corresponding":false},{"id":1110139,"name":"Xi Yang","orcid":"0000-0002-8831-7488","position":8,"is_corresponding":false},{"id":570068,"name":"Rebekah Dadey","orcid":"0000-0001-9912-7893","position":9,"is_corresponding":false},{"id":904938,"name":"Arivarasan Karunamurthy","orcid":"0000-0002-5739-4923","position":10,"is_corresponding":false},{"id":1110140,"name":"Danielle Vargas De Stefano","orcid":"0000-0002-4847-3718","position":11,"is_corresponding":false},{"id":259947,"name":"Cindy Sander","orcid":"0000-0002-4136-1342","position":12,"is_corresponding":false},{"id":562876,"name":"Sheryl Kunning","orcid":"0000-0001-7529-040X","position":13,"is_corresponding":false},{"id":268506,"name":"Yana G. Najjar","orcid":"0000-0002-0138-1664","position":14,"is_corresponding":false},{"id":259948,"name":"Diwakar Davar","orcid":"0000-0002-7846-8055","position":15,"is_corresponding":false},{"id":92112,"name":"Jason J. Luke","orcid":"0000-0002-1182-4908","position":16,"is_corresponding":false},{"id":646917,"name":"William E. Gooding","orcid":"0000-0001-9070-3559","position":17,"is_corresponding":false},{"id":109276,"name":"Tullia C. Bruno","orcid":"0000-0002-6433-0207","position":18,"is_corresponding":false},{"id":247570,"name":"John M. Kirkwood","orcid":"0000-0002-3570-4476","position":19,"is_corresponding":false},{"id":311651,"name":"Walter J. Storkus","orcid":"0000-0001-8961-4444","position":20,"is_corresponding":false},{"id":953091,"name":"Lilit Karapetyan","orcid":"0000-0001-8530-0907","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:13:52.889556Z","pmid":"37435077","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}