(1) Background: Cutaneous melanoma (CM) originates from melanocytes and causes 90% of skin cancer deaths; therefore, the comparison of different soluble and tissue markers could be valuable in the detection of melanoma progression and therapy monitoring. The present study is focused on the potential correlations between soluble S100B and MIA protein levels in different melanoma stages or with tissue expression of S100, gp100 (HMB45), and MelanA biomarkers. (2) Methods: Soluble S100B and MIA levels were evaluated by means of immunoassay methods in blood samples from 176 patients with CM, while tissue expressions of S100, MelanA, and gp100 (HMB45) were detected by means of immunohistochemistry in 76 melanomas. (3) Results: Soluble S100B correlated with MIA in stages III (r = 0.677, p < 0.001) and IV (r = 0.662, p < 0.001) but not in stages I and II; however, 22.22% and 31.98% of stage I and II patients, respectively, had high values for at least one of the two soluble markers. S100 tissue expression correlated with both MelanA (r = 0.610, p < 0.001) and HMB45 (r = 0.476, p < 0.01), while HMB45 and MelanA also significantly positively correlated (r = 0.623, p < 0.001). (4) Conclusions: Blood levels of S100B and MIA corroborated with melanoma tissue markers expression could help to improve the stratification process for patients with a high risk of tumor progression.

Background: Immune checkpoint inhibitors (ICIs) used for the treatment of advanced melanoma have yielded significant results, with long-term responses and improved survival rates, but not for all treated patients. Therefore, predictive biomarkers of response to ICI therapy have been intensively explored. Our study aimed to evaluate the dynamics of peripheral blood lymphocyte variation and their correlation with a set of related inflammatory factors in Nivolumab-treated advanced melanoma patients. Methods: The immunophenotypic assessment of peripheral blood immune cell subpopulations (CD3⁺, CD4⁺, and CD8⁺ T cells; CD19⁺ B cells; CD16⁺CD56⁺ NK cells; and CD4⁺/CD8⁺ ratio) was performed by the flow cytometry technique, concomitantly with a complete blood count; levels of S100, IL-6, and TNF-α proteins were quantified in serum by immunoassays, and lactate dehydrogenase (LDH) by a chemiluminescence assay. Results: Approximately 85% and 79% of patients recorded a trend of increasing levels of CD8⁺ lymphocytes and NK cells, respectively, during therapy. The percentage of NK cells negatively correlated with CD3⁺, CD4⁺, and CD19⁺ cells; the last three cell populations also established negative correlations with the inflammatory neutrophile/lymphocyte ratio (NLR). Furthermore, CD19⁺ cells were negatively correlated with the systemic inflammatory response index (SIRI) and systemic immune-inflammation index (SII). The evaluation of progression biomarkers showed that LDH levels directly correlated with IL-6 and S100 proteins, but no correlation was found with TNFα; IL-6 levels negatively correlated with percentages of CD3⁺, CD4⁺, and CD8⁺ lymphocytes. Conclusions: Variation in lymphocyte subpopulations during immunotherapy of advanced melanoma patients, associated with other cellular and/or molecular inflammatory markers, might provide insights about immune system response, but additional prospective studies are needed.