The Role of Ganglioside GD2 and GD3 Synthase (ST8SIA1) in the Regulation of Immune Suppression in Breast Cancer

Gangliosides are acidic glycosphingolipids involved in cell adhesion, proliferation, and modulation of signal transduction pathways. It has been reported that tumor-shed gangliosides influence the activity of immune cells including macrophages, NK cells, and T cells. GD3 synthase (GD3S) is the key enzyme that regulates the biosynthesis of the b and c series gangliosides, particularly GD3 and GD2, and studies have shown that GD3S is upregulated in most tumors and plays a role in tumor progression. Similarly, we have previously found GD3S to be significantly upregulated in GD2+ breast cancer stem cells (BCSC) compared to GD2- cells, and the knockdown of this gene prevented tumor formation in mice. Studies have also shown that GD2 is overexpressed in many cancers and serves as a tumor-associated antigen, making it a suitable target for cancer therapy and an interesting source of target for immunotherapy with the development of anti-GD2 monoclonal antibodies. Here, we demonstrate that GD3S expression associates with immune checkpoint inhibitors and its elevated expression in primary breast tumors causes a reduced immune cell infiltration into the tumors. Additionally, we have observed that GD3S regulates macrophage-mediated phagocytosis, NK cell-mediated killing and T cell cytotoxicity of breast cancer (BC) cells. Moreover, our findings reveal that the major downstream effect of GD3S is the regulation of GD2 and GD3 biosynthesis. Finally, the naxitamab antibody (humanized anti-GD2; hu3F8) enhances NK cell-mediated ADCC and macrophage-mediated ADCP in breast cancer cells and inhibits primary tumor growth in the TNBC PDX model, in the presence of macrophages and NK cells.