Differential influence of the tumour-specific non-human sialic acid containing GM3 ganglioside on CD4+CD25- effector and naturally occurring CD4+CD25+ regulatory T cells function

Abstract

Increasing evidences suggest that the aberrant expression of certain gangliosides on malignant cells could affect host's anti-tumour-specific immune responses. We have recently documented the relevance of the N-glycolylated variant of GM3 ganglioside (NGcGM3), a tumour-specific non-human sialic acid containing ganglioside, for tumour progression. However, evidences about the implication of host's immunity in NGcGM3-promoted cancer progression had not been obtained previously. In this work, we compared tumour growth of X63 myeloma cells pre-treated or not with an inhibitor of the glucosylceramide synthase enzyme, in wild or CD4+ T cell-depleted BALB/c mice. Results clearly showed a relationship between the agonistic effect of NGcGM3 in tumour growth and the presence of CD4+ T lymphocytes. For the first time, a description of a ganglioside-differential effect over purified CD4+CD25- and naturally occurring regulatory CD4+CD25+ T cells is provided. While NGcGM3 similarly down-modulated the CD4 expression in both cell populations, the inhibitory capacity of the CD4+CD25+ lymphocytes and their proliferation, induced by an anti-CD3 mAb and IL2, were not modified. In a different fashion, a reduction in proliferative capacity and a noteworthy secretion of anti-inflammatory cytokines were detected when CD4+CD25- T cells were cultured in the presence of NGcGM3. Considering the relevance of dendritic cells (DC) on primary activation of T cells, the effect of NGcGM3 over DC differentiation and TLR4-mediated maturation was also assessed. Our results indicate that NGcGM3 contributes to cancer progression mainly by influencing DC and CD4+CD25- T lymphocyte functions, rather than increasing the inhibitory capacity of naturally occurring regulatory T cells.

Immunogenicity and safety of a NeuGcGM3 based cancer vaccine: Results from a controlled study in metastatic breast cancer patients.

“…Recent results indicated that NeuGcGM3 contribute to cancer progression mainly by influencing DC and CD4 + CD25 -T lymphocyte functions, rather than increasing the inhibitory capacity of naturally occurring regulatory T cells. 6 The relevance of these three patients developed vitiligo at the lower dose, although the nominal antigen NeuGcGM3 was not present in melanocytes. Safety and immunogenicity with NeuGcGM3 vaccine treatment in advanced melanoma patients were established.…”

“…from breast cancer patients vaccinated with NeuGcGM3/VSSP plus Montanide ISA51 in a previous clinical trial. 6 Nonetheless, the molecular pathway that is activated under polyclonal NeuGcGM3-specific antibodies effect remains unclear.…”

“…The inhibitory effect of the vaccine-generated anti-NeuGcGM3 antibodies on ganglioside induced CD4 down-modulation 6 was conducted. The as regulators of cell death signaling pathways.…”

“…The high expression of this antigen specific molecule has been associated with malignant tumor progression and immunosuppressive mechanisms. 3,5,6,30 Increased levels of NeuGc-containing gangliosides have been described in human breast cancer. 4,31 The presence of large amounts of these tumor associated carbohydrate antigens on cancer cells, as…”

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

“…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. 16,17 The vaccine consisted in very small sized proteoliposomes (VSSP) obtained by the incorporation of the NGcGM3 ganglioside into the outer membrane protein (OMP) complex of Neisseria meningitides.…”