[Cancer immunotherapy: from inception to Nobel Prize].

Immunotherapy has meant a great scientific advance in the treatment of cancer in recent years, being considered as the therapeutic cornerstone of some neoplasms. However, in some types of cancer only a fraction of patients achieve benefit, posing the challenges and limitations that lead us to the need to understand the complexity of tumor biology, the microenvironment and the responsiveness of each agent. The results currently exceed what was achieved by conventional chemotherapy, although it is not yet possible to determine whether these responses are lasting or represent cure.

Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure.

Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immune-evasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation.

Oncogenic transformation tunes the cross-talk between mesenchymal stem cells and T lymphocytes.

Stem cells from mesenchymal origin (MSC) exert a plethora of immunomodulatory effects. We created a neoplastic model based on in vitro step-wise transformation to assess whether oncogenic pathways have the capacity to mould the cross-talk of MSC and lymphocytes. Neoplastic MSC exhibit an increased inhibitory effect on T cell proliferation, either directly or mediated by myeloid derived suppressor cells.

A view on EGFR-targeted therapies from the oncogene-addiction perspective.

Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies.

Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes.

Cell proliferation is accompanied by an increase in the utilization of glucose and glutamine. The proliferative response is dependent on a decrease in the activity of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)-Cdh1 which controls G1-to-S-phase transition by targeting degradation motifs, notably the KEN box. This occurs not only in cell cycle proteins but also in the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), as we have recently demonstrated in cells in culture.

Direct validation of NGcGM3 ganglioside as a new target for cancer immunotherapy.

Objective: The target concept means not only an aberrant expression of a particular molecule in tumour tissues but also evidence of a clear therapeutic advantage, as a consequence of immune-intervention, in an antigen-positive relevant tumour model. Since we reported the presence of NGcGM3 ganglioside in human breast tumours years ago and though Phase I clinical trials of a ganglioside containing vaccine have been conducted, a definitive direct validation of this peculiar molecule as target for cancer immunotherapy has remained unperformed.

Methods: Two animal models were used: leghorn chickens and C57BL/6 mice.

Role of lipopolysaccharide in the induction of type I interferon-dependent cross-priming and IL-10 production in mice by meningococcal outer membrane vesicles.

We investigated the contribution of lipopolysaccharide (LPS) to adjuvant properties of native outer membrane vesicles (NOMV), a vaccine candidate for meningococcal B disease. NOMV induce the maturation of and cytokine production by murine bone marrow-derived dendritic cells through both toll-like receptors (TLR) 2 and 4 which are mostly dependent on the signalling adaptor MyD88. NOMV are also able to induce B cell proliferation in splenocytes from LPS-hyporesponsive mice.

Towards the definition of a chimpanzee and human conserved CD6 domain 1 epitope recognized by T1 monoclonal antibody.

Scavenger receptor cysteine-rich (SRCR) domains are evolutionally conserved modules that display complex structures stabilized by key amino acids, while some other residues have evolved with a relative independence, thus allowing the functional diversity of these receptors. CD6, a highly glycosylated membrane protein predominantly expressed on lymphocytes, contains three SRCR domains. The lack of CD6 domain crystal structure has limited the characterization of the binding sites for the interacting molecules.

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity.

Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid-containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4(+) T lymphocytes) that expressed the antigen.

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.

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.

Gangliosides as immunomodulators.

Gangliosides are glycosphingolipids expressed at the outer leaflet of the plasmatic membrane of cells from vertebrate organisms. These molecules exert diverse biological functions including modulation of the immune system responses. Aberrant expression of gangliosides has been demonstrated on malignant cells.

Very small size proteoliposomes derived from Neisseria meningitidis: an effective adjuvant for dendritic cell activation.

Recent findings in the interactions between pathogens and the innate immune system, particularly with dendritic cells (DC), have opened new opportunities for adjuvants designs. We have elaborated a new approach, in which gangliosides are incorporated into the outer membrane complex of Neisseria meningitidis to form very small size proteoliposomes (VSSP). VSSP demonstrated a unique ability to render highly tolerated gangliosides immunogenic.

Very small size proteoliposomes derived from Neisseria meningitidis: An effective adjuvant for generation of CTL responses to peptide and protein antigens.

The development of potent adjuvants, conditioning innate and adaptative immunity, particularly CTL responses, has become currently a hot point in the rational design of vaccines for cancer immunotherapy. We have described a new approach, in which gangliosides are incorporated into vesicles from Neisseria meningitidis to form Very Small Size Proteoliposomes (VSSP). VSSP is a good alternative to the existing adjuvants for use in whole cells vaccines since it promotes 80% tumour rejection and growing delay in the CT26 and F3II tumour models respectively.

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

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.

Very small size proteoliposomes derived from Neisseria meningitidis: an effective adjuvant for Th1 induction and dendritic cell activation.

Recent findings about pathogens and innate immune system interactions have opened new opportunities for adjuvants designs. We have elaborated a new approach, in which gangliosides are incorporated into the outer membrane complex of Neisseria meningitidis (Nm) to form very small size proteoliposomes (VSSP). VSSP, used as monotherapy, demonstrated a unique ability to render immunogenic highly tolerated gangliosides.