Abstract B21: Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1

Abstract

Abstract Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attributed to reduced binding of galectin-3 with C4S, and the increase of MMP2 was attributed to inhibition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced by siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was obtained from the biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced by siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein by ELISA (p<0.001). In a metastatic melanoma cell line, PD-L1 increased from baseline value of 407 ± 34 pg/mg to 462 ± 26 pg/mg when ARSB was silenced. These findings indicate that decline in ARSB contributes to the progression of metastatic melanoma and to the immune checkpoint responsiveness of the melanoma cells. Further studies are required to determine how ARSB leads to increased PD-L1 expression and how treatment with recombinant ARSB can retard the progression of melanoma. Citation Format: Joanne K. Tobacman, Sumit Bhattacharyya, Leo Feferman. Arylsulfatase B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B21.