Biology of GD2 ganglioside: implications for cancer immunotherapy

Abstract

Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane. Gangliosides are produced through sequential steps of glycosylation and sialylation. This diversity of composition is reflected in differences in expression patterns and functions of the various gangliosides. Ganglioside GD2 designates different subspecies following a basic structure containing three carbohydrate residues and two sialic acids. GD2 expression, usually restrained to limited tissues, is frequently altered in various neuroectoderm-derived cancers. While GD2 is of evident interest, its glycolipid nature has rendered research challenging. Physiological GD2 expression has been linked to developmental processes. Passing this stage, varying levels of GD2, physiologically expressed mainly in the central nervous system, affect composition and formation of membrane microdomains involved in surface receptor signaling. Overexpressed in cancer, GD2 has been shown to enhance cell survival and invasion. Furthermore, binding of antibodies leads to immune-independent cell death mechanisms. In addition, GD2 contributes to T-cell dysfunction, and functions as an immune checkpoint. Given the cancer-associated functions, GD2 has been a source of interest for immunotherapy. As a potential biomarker, methods are being developed to quantify GD2 from patients’ samples. In addition, various therapeutic strategies are tested. Based on initial success with antibodies, derivates such as bispecific antibodies and immunocytokines have been developed, engaging patient immune system. Cytotoxic effectors or payloads may be redirected based on anti-GD2 antibodies. Finally, vaccines can be used to mount an immune response in patients. We review here the pertinent biological information on GD2 which may be of use for optimizing current immunotherapeutic strategies.

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

“…GD2 is a disialoganglioside that is biosynthesized from the precursor gangliosides GD3/GM3 by β-1,4-N-acetylgalactosaminyltransferase (B4GALNT1, GD2 synthase) ( Figure 6A ). The expression of GD2 in normal tissues is restricted to the brain, peripheral pain fibers, and skin melanocytes, but it is abundantly expressed in neuroectodermal tumors including neuroblastoma 70 . The application of anti-GD2 immunotherapy has greatly improved the survival of high-risk neuroblastoma patients when it is combined with a differentiating agent and chemotherapy 71–73 .…”

Revolutionizing pediatric neuroblastoma treatment: unraveling new molecular targets for precision interventions

“…One of these immunotherapies is centered on utilizing mAbs to target GD2, which is found in higher quantities than in a control group in cases of NB. GD2 is a disialoganglioside present on the outer surface of all NB cells ( Tibbetts et al, 2022 ; Machy et al, 2023 ). Including monoclonal antibodies like anti-GD2 in initial and recurrent treatment strategies has significantly improved survival rates and transformed the outlook for children with HRNB ( Anderson et al, 2022 ).…”

From mechanism to therapy: the journey of CD24 in cancer

“…As a disialoganglioside, GD2 is notably overexpressed in neuroblastoma, sarcomas, gliomas, and neuroendocrine tumors (97,102,103). The significance of GD2 as a cancer target has been extensively reviewed (103,104). GD2 antibodies lies in their ability to bind selectively to the GD2 antigen on cancer cells, thereby facilitating the immune system recognition and destruction of these cells.…”