IMMUNOSUPPRESSION BY HUMAN GANGLIOSIDES .1. RELATIONSHIP OF CARBOHYDRATE STRUCTURE TO THE INHIBITION OF T-CELL RESPONSES

Causes of cellular immunodeficiency frequently associated with cancer remain poorly understood. One possible mechanism is tumor cell membrane shedding of immunosuppressive molecules, such as the sialic acid-containing glycosphingolipids, gangliosides. To explore this interesting hypothesis and establish structure-activity relationships, we examined the effects of a series of highly purified human gangliosides on T cell function. In all, ten individual molecular species of two major biosynthetic pathways were compared for their ability to inhibit human T cell proliferative responses. They include G(M1), G(D1a), G(D1b), and G(T1b) (the predominant normal brain species), and G(M4), G(M3), G(M2), G(D3), G(D2) and G(Q1b). Strikingly, each HPLC-purified molecule, from the simplest monosialoganglioside to the most complex polysialoganglioside, had potent inhibitory activity; even the ganglioside with the most elemental carbohydrate structure (G(M4), one sialic acid linked to a monosaccharide) strongly inhibits T cell proliferative responses to tetanus toxoid (ID90 = 1.5-mu-M). The data also reveal a complex interplay between elements of oligosaccharide structure in determining immunosuppressive activity. Sialic acid is critical to maximal activity, and (i) immunosuppression is most potent in gangliosides containing a terminal sialic acid. (ii) Total desialylation almost abolishes activity and (iii) partial alteration (lactone formation) reduces activity. (iv) Activity is generally but not always higher with higher numbers of sialic acid residues/molecule, and (v) some larger neutral glycosphingolipids retain measurable immunosuppressive activity. Overall, the potent inhibition by gangliosides supports the hypothesis that shedding of these molecules by tumors creates a highly immunosuppressive microenvironment around the tumor, thereby inhibiting the function of infiltrating host leukocytes and contributing to diminished T cell responses in cancer.