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

Vaccine Department, Centre of Molecular Immunology, 216 esq 15, Atabey, Playa, 16040, C. Habana, Cuba.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 05/2006; 55(4):443-50. DOI: 10.1007/s00262-005-0041-6
Source: PubMed


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.

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Available from: Joel De León, Aug 17, 2015
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    • "Gangliosides have been found to shift the cytokine profile from Th1 toward the Th2 in affected cells (Crespo et al., 2006). Negative modulation of CD4 molecule on T lymphocytes has been described for both the N-acetylated (Sorice et al., 1995) and the N-glycolylated variants (de Leon et al., 2006) of GM3 ganglioside. Gangliosides have been reported to block the nuclear translocation of NF-κB in human monocytes and dendritic cells (Caldwell et al., 2003). "
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    ABSTRACT: Surgery, chemotherapy, and radiation therapy are standard modalities for cancer treatment, but the effectiveness of these treatments has reached a plateau. Thus, other strategies are being explored to combine with the current treatment paradigms in order to reach better clinical results. One of these approaches is the active immunotherapy based on the induction of anti-tumor responses by anti-idiotypic vaccination. This approach arose from Jerne's idiotypic network theory, which postulates that B lymphocytes forms a functional network, with a role in the establishment of the immune repertoires, in the regulation of natural antibody production and even in the establishment of natural tolerance. Due to the large potential diversity of the immunoglobulin variable regions, the idiotypes repertoire can mimic the universe of self and foreign epitopes, even those of non-protein nature, like gangliosides. Gangliosides are sialic acid-containing glycolipids that have been considered attractive targets for cancer immunotherapy, based on the qualitative and quantitative changes they suffer during malignant transformation and due to their importance for tumor biology. Although any idiotype could be able to mimic any antigen, only those related to antigens involved in functions relevant for organism homeostasis, and that in consequence has been fixed by evolution, would be able not only to mimic, but also to activate the idiotypic cascades related with the nominal antigen. The present review updates the results, failures and hopes, obtained with ganglioside mimicking anti-idiotypic antibodies and presents evidences of the existence of a natural response against gangliosides, suggesting that these glycolipids could be idiotypically relevant antigens.
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    • "However, the presence of NeuGc-neuraminic acid residues has been reported in different human tumors, detected by antibodies and by chemical analysis (Higashi et al., 1984, 1988; Hirabagashi et al., 1987; Miyake et al., 1990; Devine et al., 1991; Marquina et al., 1996; Malykh et al., 2001; van Cruijsen et al., 2009; Scursoni et al., 2010), where they are known to be immunogenic (Nguyen et al., 2005). Additionally, recent experimental data suggest that NeuGcGM3 ganglioside is relevant for tumor progression (de León et al., 2006). "
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    ABSTRACT: Neu-glycolyl (NeuGc)-containing gangliosides are attractive targets for immunotherapy with anti-idiotype mAbs, because these glycolipids are not normal components of the cytoplasmic membrane in humans, but their expression has been demonstrated in several human malignant tumors. Racotumomab is an anti-idiotype mAb specific to P3 mAb, an antibody which reacts to NeuGc-containing gangliosides, sulfatides, and other antigens expressed in tumors. Preparations containing racotumomab were able to induce a strong anti-metastatic effect in tumor-bearing mice. Different Phase I clinical trials have been conducted in patients with advanced melanoma, breast cancer, and lung cancer. The results of these clinical trials demonstrated the low toxicity and the high immunogenicity of this vaccine. The induced antibodies recognized and directly killed tumor cells expressing NeuGcGM3. A Phase II/III multicenter, controlled, randomized, double blind clinical trial was conducted to evaluate the effect of aluminum hydroxide-precipitated racotumomab vaccine in overall survival in patients with advanced non-small cell lung cancer. The clinical results of this study showed a significant clinical benefit in the patients who were treated with the anti-idiotype vaccine.
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