Role of immune response, inflammation and tumor immune response-related cytokines/chemokines in melanoma progression.

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated proportions of immune cell subsets in melanoma tumors from TCGA, followed by evaluation of association between cytokine/chemokine expression and these subsets. We then investigated association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated immune cell TIL score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA-seq estimation of T-cell subset with pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P<0.05). In multivariable analysis, higher expression levels of cytokines IFNG and TGFB1, but not chemokines, were associated with improved OS. Higher expression level of CD8+ T cell subset was also associated with improved OS (HR = 0.06, 95% CI = 0.01-0.35, P = 0.002). Finally, multivariable analysis showed that patients with brisk TIL score had improved melanoma-specific survival compared to those with non-brisk score (HR = 0.51, 95% CI = 0.27-0.98, P = 0.0423). These results suggest that expression of specific tumor cytokines represent important biomarkers of melanoma immune response.