Little is known about the infiltrative pattern of innate immune cells in primary melanoma compared with their paired metastases and in BRAFV600E-mutated tumors. Therefore, our aim was to characterize the inflammatory microenvironment in primary ulcerated and nonulcerated melanomas and paired metastases, to investigate the relation between inflammation and BRAFV600E mutation in primary melanoma and paired metastases, and to evaluate the effect of the analyzed biomarkers on melanoma-specific survival. A total of 385 primary tumors and 96 paired metastases were stained with immunohistochemistry for BRAFV600E, CD163+ macrophages, CD123+ plasmacytoid dendritic cells, CD66b+ neutrophils, and E-cadherin and estimated using objective computer-assisted image analysis. BRAFV600E was semiquantitatively scored as either present or absent. In metastases of nonulcerated melanomas, we observed higher neutrophil (P=0.02) and macrophage (P=0.01) numbers. In the metastases of ulcerated melanomas, we found a higher number of macrophages (P<0.0001). Increase in the neutrophil numbers in the metastases was associated with poor patient survival after first relapse (hazard ratio=1.19, 95% confidence interval: 1.03–1.38, P=0.02). BRAFV600E-positive primary tumors (P=0.02) and metastases (P=0.01) exhibited increased plasmacytoid dendritic cell numbers compared with BRAFV600E-negative tumors. Lastly, primary melanomas in men had higher neutrophil numbers than women (P≤0.0001), and men had worse melanoma-specific survival (hazard ratio=1.52, 95% confidence interval: 1.04–2.21, P=0.03). Our data show that melanoma metastases are densely infiltrated with neutrophils, which affects survival. Our results also highlight the importance of recognizing the presence of inflammatory cells in the metastases as a prognostic marker, and that they may potentially be used to improve the precision of immunotherapy and BRAFV600E targeted therapy.
Checkpoint inhibitors are novel and promising treatment options for different types of cancer. Programmed cell death 1 (PD-1) inhibitors, such as pembrolizumab, have been shown to significantly raise the survival rates of disseminated malignant melanoma (MM). Autoimmune adverse reactions are very common in checkpoint inhibitors. We present 2 cases of bullous pemphigoid, as adverse reactions to pembrolizumab-treated MM.
Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders.
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