Immunization with a GM3 ganglioside nanoparticulated vaccine confers an effector CD8+ T cells-mediated protection against melanoma B16 challenge

Abstract

Preventive immunotherapy is an attractive strategy for patients at a high risk of having cancer. The success of prophylactic cancer vaccines would depend on the selection of target antigens that are essential for tumour growth and progression. The overexpression of GM3 ganglioside in murine and human melanomas and its important role in tumour progression makes this self antigen a potential target for preventive immunotherapy of this neoplasm. We have previously shown that preventive administration of a GM3-based vaccine to C57BL/6 mice elicited the rejection of the GM3 positive-B16 melanoma cells in most of the animals. Despite the crucial role of cellular immune response in tumour protection, the involvement of T cells in anti-tumour immunity of ganglioside vaccines is not described. Here, we examined the mechanisms by which this immunogen confers tumour protection. We have found that induction of anti-GM3 IgG antibodies correlated with tumour protection. Surprisingly, CD8(+) T cells, but not NK1.1(+) cells, are required in the effector phase of the antitumour immune response. The depletion of CD4(+) T cells during immunization phase did not affect the anti-tumour activity. In addition, T cells from surviving-immunized animals secreted IFNgamma when were co-cultured with IFNalpha-treated B16 melanoma cells or DCs pulsed with melanoma extract. Paradoxically, in spite of the glycolipidic nature of this antigen, these findings demonstrate the direct involvement of the cellular immune response in the anti-tumour protection induced by a ganglioside-based vaccine.

Chemoenzymatic synthesis and biological evaluation of ganglioside GM3 and lyso-GM3 as potential agents for cancer therapy

“…GM3, the first and simplest member in the metabolic series of a GSLs family, contains a single terminal sialic acid, lactose and ceramide (Scheme 1). Aberrant expression of GM3 has been found to be associated with glycosphingolipid storage diseases and cancer progression [6,7].…”

Synthesis of a conjugate of 3´-sialyllactoside with recombinant flagellin as a carrier protein and assessment of its immunological activity in comparison with that of a similar hemocyanin-based conjugate

“…17 Due to increased expression of GM3 on highly metastatic cancer cells allows to regard this ganglioside as a prospective target 18 for the immunotherapy. This sug gestion was confirmed by clinical trials 19 of the melanoma vaccine for stage II melanoma patients, which showed 60% increase of 5 year survival rates.…”

Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy

“…It seems more logical to develop human monoclonal IgG antibodies. The only caveat to this assumption is the recent demonstration that glycolipid vaccines can also stimulate cellular immunity resulting in tumour regression mediated by CD8 cytotoxic T cells [111]. The combination of antibody and cellular immunity may prove to have strong anti‐tumour efficacy.…”