Prognostic significance of CD163 expression and its correlation with cyclooxygenase-2 and vascular endothelial growth factor expression in cutaneous melanoma

Abstract

In several cancers, tumor progression is associated with the infiltration of tumor-associated macrophages (TAMs). The aim was to evaluate the prognostic significance of expression of CD163 and CD68 (TAMs’ markers) and their correlation with vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) expression in cutaneous melanoma. Diagnostic tissues from 102 patients of cutaneous melanoma were evaluated by immunohistochemistry for their CD68, CD163, VEGF, and COX-2 expression. Correlations between the proteins were then investigated. Clinicopathological features, overall survival (OS), and progression-free survival were analyzed in terms of the expression of these proteins. CD163, but not CD68, expression correlated with VEGF and COX-2 expression. High expression for CD163 was associated with a deeper Breslow thickness and an advanced stage of the disease. High expression of CD163 was associated with lower OS. No significant differences were noted in CD68 expression between the clinicopathological variables and the OS. COX-2 expression was associated with a deeper Breslow thickness and a higher frequency of lymph node involvement. Multivariate analysis revealed that CD163 expression and COX-2 expression were independent prognostic markers of lower survival outcomes. Our data confirmed that CD163 expression provides independent prognostic information in cutaneous melanoma. The correlation of CD163 with VEGF and COX-2 expression suggests various tumor-promoting actions of CD163-positive TAMs.

Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma

“…In our previous study, high CD163 expression was associated with lower OS, suggesting the prognostic significance of CD163 expression in cutaneous melanoma [16]. We observed that CD163 expression correlated with VEGF and COX-2 expression [16].…”

“…In our previous study, high CD163 expression was associated with lower OS, suggesting the prognostic significance of CD163 expression in cutaneous melanoma [16]. We observed that CD163 expression correlated with VEGF and COX-2 expression [16]. However, limited information is available about the expression of CD163 and its relationship with immune checkpoint molecules, particularly PD-1 and LAG-3.…”

“…CD163 is a scavenger receptor for haptoglobin-hemoglobin complexes [16] specifically expressed on M2 macrophages. This marker has been investigated as an indicator of poor prognosis in various tumors, including melanoma [16], breast [17], gastric [18], ovarian [19], pancreatic cancer [20], as well as head and neck squamous carcinoma [21]. Recent studies in advanced cutaneous melanoma also revealed that increased serum levels of CD163 were related to positive response to anti-PD-1 antibody [22].…”

Differential association of CD68+ and CD163+ macrophages with macrophage enzymes, whole tumour gene expression and overall survival in advanced melanoma

“…The contrasting trends of CD68 + macrophages and CD163 + macrophages against Breslow depth is striking in suggesting a differential expression pattern, albeit with the former being non-significantly correlated. A recent study by Lee et al 29 provides corroborating evidence that increased CD163 + cell infiltration is associated with increased Breslow depth. 29 There is much evidence that tumours exert a strong polarising effect on recruited cells, and it remains to be determined whether the CD68 + and CD163 + infiltration is reflective of differential recruitment, or a system in which CD68 + cells are recruited and polarised to a CD163 + phenotype, which is less functionally active in the parameters we observed, such as arginase and iNOS activity and influencing gene expression within the tumour.…”

“…A recent study by Lee et al 29 provides corroborating evidence that increased CD163 + cell infiltration is associated with increased Breslow depth. 29 There is much evidence that tumours exert a strong polarising effect on recruited cells, and it remains to be determined whether the CD68 + and CD163 + infiltration is reflective of differential recruitment, or a system in which CD68 + cells are recruited and polarised to a CD163 + phenotype, which is less functionally active in the parameters we observed, such as arginase and iNOS activity and influencing gene expression within the tumour. 30 – 32 This system would explain both the increased prevalence of CD68 + macrophages in less progressed tumours and increased accumulation of CD163 + macrophages in more advanced tumours.…”