Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum are prognostic of melanoma patient outcomes

• Published in: Frontiers in immunology Vol. 14; p. 1171978
• Main Authors: Karapetyan, Lilit, AbuShukair, Hassan M, Li, Aofei, Knight, Andrew, Al Bzour, Ayah Nedal, MacFawn, Ian P, Thompson, Zachary J, Chen, Ann, Yang, Xi, Dadey, Rebekah, Karunamurthy, Arivarasan, De Stefano, Danielle Vargas, Sander, Cindy, Kunning, Sheryl R, Najjar, Yana G, Davar, Diwakar, Luke, Jason J, Gooding, William, Bruno, Tullia C, Kirkwood, John M, Storkus, Walter J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 22.06.2023
• Subjects: Aged; APRIL; cytokine; Cytokines; Female; Gene Expression Profiling; Genomics; Humans; Immunology; lymphoid aggregate; Male; melanoma; Melanoma - genetics; Middle Aged; Prognosis; tertiary lymphoid structure; TNFSF13; Tumor Microenvironment - genetics; cytokine; tertiary lymphoid structure; chemokine; TNFSF13; survival; melanoma; lymphoid aggregate; APRIL
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1171978

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. 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. 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 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 tumor transcript levels in a 3-gene index revealed that high 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 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.