Role of tumour-associated N-glycolylated variant of GM3 ganglioside in cancer progression: effect over CD4 expression on T cells

Abstract

Gangliosides have diverse biological functions including modulation of immune system response. These molecules are differentially expressed on malignant cells compared with the corresponding normal ones and are involved in cancer progression affecting, in different ways, the host's anti-tumour specific immune responses. Although in humans the N-glycolylated variant of GM3 ganglioside is almost exclusively expressed in tumour tissues, the significance of this glycolipid for malignant cell biology remains obscure, while for NAcGM3 strong immune suppressive effects have been reported. The present work demonstrates, for the first time, the capacity of NGcGM3 ganglioside to down-modulate CD4 expression in murine and human T lymphocytes, especially in non-activated T cells. Thirty and tenfold reductions in CD4 expression were induced by purified NGcGM3 ganglioside in murine and human T lymphocytes, respectively. The CD4 complete recovery in these cells occurred after 48 h of ganglioside removal, due to neo-synthesis. Restored T cells kept similar sensitivity to ganglioside-induced CD4 down-modulation after a new challenge. In addition, a clear association between NGcGM3 insertion in lymphocyte plasma membranes and the CD4 down-modulation effect was documented. Notably, a possible role of this ganglioside in tumour progression, taking advantage of the X63 myeloma model, was also outlined. The relevance of these findings, characterizing NGcGM3 as a possible tumour immunesurveillance inhibitor and supporting the reason for its neo-expression in certain human cancers, is contributing to this unique heterophilic ganglioside validation as target for cancer immunotherapy.

Molecular subtyping of metastatic melanoma based on cell ganglioside metabolism profiles

“…Mouse B16 melanoma cells loaded with Neu5Gc-GM3 showed more lung metastases and increased tumor burden in subcutaneous implants [50]. Moreover, on the contrary of Neu5Ac-GM3, Neu5Gc-GM3 did not inhibit EGF-induced EGFR phosphorylation in A431 cells [51] and down-modulated CD4 molecule in T lymphocytes [52] and dendritic cell differentiation [53]. To further confirm the involvement of GM3 and Neu5Gc-GM3 in melanoma aggressiveness, we demonstrated that a clone isolated from a single melanoma cell line and endowed with higher adhesive and invasive potential, showed a ganglioside pattern composed only by GM3, mainly in the form of Neu5Gc-GM3.…”

Induction of leukocyte infiltration at metastatic site mediates the protective effect of NGcGM3-based vaccine

“…7,8 N-glycolyl (NGc) gangliosides, and particularly NGcGM3, have received attention as a privileged target for cancer therapy. 9 NGcGM3 contributes to cancer progression, not only by influencing dendritic cell differentiation and maturation, but also down-modulating the CD4 expression in T cells 10 and impairing CD4 + CD25 -T lymphocyte functions. 11 Many clinical trials have been performed with a NGcGM3-containing vaccine for the immunotherapy of melanoma [12][13][14][15] and breast cancer.…”

“Lost sugars” — reality of their biological and medical applications

“…In addition to changes in the presentation of Neu5Ac, tumour cells also accumulate large amounts of the non-human Neu5Gc that originates from digested food [7,34]. Additionally, an immunomodulatory effect for Neu5Gc has been demonstrated because the ganglioside Neu5GcGM3 induces CD4 down-modulation on T cells [74]. As was previously suggested, antiNeu5Gc antibodies that are present in the circulation of patients can generate only a weak immune response that enhances leukocyte infiltration and angiogenesis, thus stimulating tumour growth.…”