Molecular Recognition of Gangliosides and Their Potential for Cancer Immunotherapies

Abstract

Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell–cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research.

Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer

“…These different functions are mainly supported by the glycan moiety, and changes in the structure of gangliosides can occur under pathological conditions, including neurodegenerative disorders and cancers [69,70,71]. In particular, the neo-expression of disialogangliosides has been demonstrated in several neuroectoderm-derived tumors in which they play a key role in invasion and metastasis [72], making disialogangliosides attractive target molecules for cancer immunotherapy [73,74]. …”

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

“…This phenomenon has been observed in several types of human cancers (for review, see ref. 98 98 ). The soluble gangliosides shed into the tumor microenvironment can dysregulate T-cell function in multiple ways.…”

“…11 Tumor cells utilize a number of altered metabolic pathways to contribute to an unfavorable environment for T-cell expansion. 55,79 Another mechanism used by tumors to dysregulate T-cell function 98,118,146,167,175 or induce T-cell apoptosis 10,201,204,209 is the production and secretion of immunosuppressive factors into the microenvironment. Finally, tumors can prolong their survival by overexpressing various antiapoptotic proteins.…”

Gangliosides in breast cancer: New perspectives

“…Innovative therapeutic tools based on the use of anti tumor associated ganglioside mAbs have been developed and are currently under investigation in preclinical or clin ical studies, especially in the field of neuroectoderm relat ed cancers (melanoma, neuroblastoma, small cell lung cancer) [7,8]. As an example, anti G D2 clinical trials for neuroblastoma have confirmed the efficacy of anti G D2 antibody immunotherapy for this rare but often lethal childhood cancer [91].…”

“…These different functions are mainly supported by the glycan moiety, and changes in the structure of gangliosides can occur under pathological conditions, including athero sclerosis, neurodegenerative disorders, and cancers [3 5]. In particular, the neo expression of disialogangliosides has been demonstrated in several neuroectoderm derived tumors in which they play a key role in invasion and metastasis [6], making disialogangliosides attractive tar get molecules for cancer immunotherapy [7,8].…”