Abstract The chondroitin 4-sulfate (C4S) sulfatase Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) inhibits the growth and improves survival of C57BL/6J mice with B16F10 subcutaneous melanomas, inhibits the growth of A375 human melanomas in humanized mice with PBMC implants, and reduces the progression of metastatic pulmonary melanomas in the B16F10 syngeneic mouse model. Cleaved caspase-3 is enhanced by treatment with rhARSB and is mediated by increased expression of the E3 ubiquitin ligase constitutive photomorphogenic (COP)1, which reduces nuclear ETS-1 and thereby BCL2 expression. Combined treatment of B16F10 pulmonary melanomas by rhARSB and Pembrolizumab leads to greater increase in cleaved caspase-3 and greater decline in Bcl2, but no further increase in COP1 than by rhARSB alone. Similarly, in cultured A375 cells, cleaved caspase-3 is increased and BCL2 is reduced further by combined treatment of rhARSB and Pembrolizumab in the presence of PBMC, without further increase in COP1. The greater decline in Bcl2 is attributable to effects of rhARSB and Pembrolizumab in the presence of PBMC on Granzyme B. In contrast to no effect of Pembrolizumab, rhARSB reduces expression of the matrix metalloproteinases MMP2 and MMP9 in A375 melanoma cells and in B16F10 pulmonary melanomas, leading to decline in invasiveness. The mechanism by which ARSB regulates MMP expression is attributable to rhARSB-mediated decline in chondroitin 4-sulfate binding with SHP2, leading to declines in ERK1/2 phosphorylation, nuclear c-Myc-DNA-binding, and MMP2 and MMP9 promoter activation. In the B16F10 pulmonary melanomas, the combination of Pembrolizumab and rhARSB increased the mRNA expression of MCP1 and IL-10 and reduced the expression of KC and IL-6, more than either treatment alone. ARSB alone increased IL-17α and TNFα, which was reduced by Pembrolizumab and overall by their combination. The combined effects of rhARSB and Pembrolizumab demonstrate synergism which may be of significant clinical benefit. Enhanced apoptosis mediated by different Bcl2 regulatory mechanisms, decline in matrix metalloproteinases and associated invasiveness of tumor cells due to signaling effects of rhARSB, as well as combined effects on cytokine expression are anticipated to inhibit melanoma progression. Citation Format: Joanne Kramer Tobacman, Insug O-Sullivan, Sumit Bhattacharyya. Effects of arylsulfatase B and pembrolizumab on the progression of syngeneic B16F10 metastatic pulmonary melanomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 579.
Tobacman et al. (Fri,) studied this question.