Bolutyfe Oderinde (Advisor: Venkata Lokesh Battula, PhD)

The Role of Ganglioside 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 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 its knockdown 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 reduced immune cell infiltration. Additionally, we observed that GD3S regulates macrophage-mediated phagocytosis, NK cell-mediated killing and T cell-mediated cytotoxicity of breast cancer (BC) cells. Moreover, lipidomic analysis identified GD2 as the major downstream effector ganglioside in the ganglioside biosynthesis pathway. Targeting GD2 with naxitamab (humanized anti-GD2 mAb; hu3F8) effectively inhibited breast cancer growth by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), underscoring its therapeutic potential in treating GD2⁺ breast cancer.

Advisory Committee:

• Venkata Lokesh Battula, PhD, Chair
• Chandra Bartholomeusz, PhD
• Joya Chandra, PhD
• Bisrat Debeb, DVM, PhD
•  Melinda Yates, PhD

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Meeting ID: 841 4738 2620

Password: 740496