Role of Immune Response, Inflammation, and Tumor Immune Response-Related Cytokines/Chemokines in Melanoma Progression

Abstract

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated the proportions of immune cell subsets in melanoma tumors from The Cancer Genome Atlas, followed by evaluation of the association between cytokine/chemokine expression and these subsets. We then investigated the association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated the immune cell tumor-infiltrating lymphocyte (TIL) score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA sequencing estimation of T-cell subset and pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, and 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 IFN-γ and TGFB1, but not chemokines, were associated with improved overall survival. A higher expression level of CD8⁺ T-cell subset was also associated with improved overall survival (hazard ratio [HR] = 0.06, 95% confidence interval [CI] = 0.01-0.35, P = 0.002). Finally, multivariable analysis showed that patients with a brisk TIL score had improved melanoma-specific survival than those with a nonbrisk score (HR = 0.51, 95% CI = 0.27-0.98, P = 0.0423). These results suggest that the expression of specific tumor cytokines represents important biomarkers of melanoma immune response.