Correlation of MET and PD-L1 Expression in Malignant Melanoma

Abstract

The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, programmed death-ligand 1 (PD-L1), with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions, and in a human melanoma tissue microarray containing one hundreds melanocytic lesions, including primary cutaneous melanomas, primary mucosal melanomas, metastatic melanomas and benign melanocytic nevi as controls. After color deconvolution, each core was segmented to isolate staining and calculate the percentage of positive cells. Overall, MET expression was higher in tumors with increased PD-L1 expression. Moreover, a robust correlation between MET and PD-L1 expression was found in samples from metastatic melanoma and not in primary cutaneous or mucosal melanoma. These data suggest that relative expression levels of these proteins in combination is a marker of advanced disease and testing for expression of these markers should be considered in patients with melanoma.

Keywords: MET; PD-L1; melanoma; metastasis.

Figure 1

Histopathology images of MET and programmed death-ligand 1 (PD-L1) expression levels in a representative primary melanoma (A-375, panel A) and a metastatic melanoma (SH-4, panel B) cell lines. Hematoxylin and eosin (H&E), MET, and PD-L1 immunostained slides from the cell microarray (CMA) are represented (full cores, 4×; insets, 40×), as well as color-deconvolved images for MET (MET-d) and PD-L1 (PD-L1-d). Boxplot with the box representing the interquartile range and a dark line representing median MET and PD-L1 in seven primary melanomas and 11 metastatic melanomas (C). Correlation of MET and PD-L1 in primary and metastatic cell lines, with Pearson’s r values and 95% confidence interval (D).

Figure 2

MET and PD-L1 expression in a representative benign nevus, primary cutaneous melanoma, metastatic melanoma, and primary mucosal melanoma. Hematoxylin and eosin (H&E), MET, and PD-L1 immunostained slides from the tissue microarray (TMA) are represented (full cores, 4×; insets, 40×), as well as color-deconvolved images for MET (MET-d) and PD-L1 (PD-L1-d) (panel A). Boxplot with the box representing the interquartile range and a dark line representing median MET and PD-L1 in benign nevi, primary cutaneous melanoma, metastatic melanoma, and primary mucosal melanoma (panel B).

Figure 3

Correlation of MET and PD-L1 in benign nevi, primary cutaneous melanoma, metastatic melanoma, and primary mucosal melanoma, with Pearson’s r values and 95% confidence interval.