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Functional Tregs play a key role in tumor development and progression, representing a major barrier to anticancer immunity. The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood. Herein, by using NMR, chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses, we demonstrate that the tumoral carbohydrate A10 (Ca10), a cell-surface carbohydrate derived from Ehrlich’s tumor (ET) cells, is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs. Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming, PD-L1, IL-10, and IDO. Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features. In solid ET-bearing mice, we found positive correlations between Ca10 serum levels, tumor size and splenic Treg numbers. Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice. Remarkably, we provide evidence supporting the presence of a circulating human Ca10 counterpart (Ca10H) and show, for the first time, that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals. Of note, these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases. Collectively, we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer. The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.

En las últimas décadas, la inmunoterapia ha irrumpido con fuerza como alternativa para tratar el cáncer, superando las limitaciones de los tratamientos convencionales. Este tipo de terapia es capaz de modular el potencial del sistema inmunitario para la inducción de respuestas antitumorales. Un tipo de inmunoterapia son las vacunas antineoplásicas, las cuales pueden ayudar a tratar o prevenir ciertos tipos de cáncer. Durante la tumorogénesis, las células pueden sufrir modificaciones en los proteoglicanos presentes en el glicocálix mediante procesos de glicosilación incompleta o aberrante, dando lugar a nuevos antígenos potencialmente reconocibles por el sistema inmunitario. Este tipo de antígenos tumorales juegan un papel importante en la metástasis de células tumorales y la transducción de señales, y la sobreexpresión de éstos en la superficie celular se correlaciona frecuentemente con mal pronóstico. Un ejemplo de ello es el antígeno Ca10, una macromolécula de alto peso molecular caracterizada como un proteoglicano de heparán sulfato que contiene el epítopo de naturaleza sacarídica definido por el anticuerpo monoclonal A10. Este epítopo de tipo carbohidrato se encuentra expresado en la superficie de membrana de células del tumor murino de Ehrlich (ET) y en algunos tumores epiteliales humanos de origen glandular. Además, también se detecta en el suero de determinados pacientes con estos tipos de tumores. Por todo ello, el Ca10 es una potencial diana para el desarrollo de una vacuna antitumoral. Para su desarrollo, el Ca10 fue formulado con un potencial nuevo adyuvante basado en micropartículas de silicio mesoporoso (MSMPs-Ca10), demostrando inducir una eficiente respuesta humoral y de resistencia tumoral. Las micropartículas mesoporosas de silicio (MSMPs) ofrecen grandes ventajas como adyuvantes: poseen un tamaño de poro ajustable y una naturaleza biocompatible y biodegradable. Sabemos del gran potencial de estos materiales para estimular células presentadoras de a, In recent decades, immunotherapy has strongly emerged as an alternative for treating cancer, overcoming the limitations of conventional treatments. This type of therapy can modulate the potential of the immune system to induce antitumor responses. One type of immunotherapy is antineoplastic vaccines, which can help treat or prevent certain types of cancer.During tumorogenesis, cells can undergo modifications in the proteoglycans present in the glycocalyx, through incomplete or aberrant glycosylation processes, giving rise to new antigens potentially recognizable by the immune system. These types of tumor antigens play an important role in tumor cell metastasis and signal transduction, and their overexpression on the cell surface frequently correlates with poor prognosis. An example of this is the Ca10 antigen, a high molecular weight macromolecule characterized as a heparan sulfate proteoglycan containing the saccharide epitope defined by the monoclonal antibody A10. This carbohydrate-type epitope is expressed on the membrane surface of murine Ehrlich tumor (ET) cells and in some human epithelial tumors of glandular origin. In addition, it is also detected in the serum of certain patients with these types of tumors. Therefore, Ca10 is a potential target for the development of an anti-tumor vaccine. For its development, Ca10 was formulated with a potential new adjuvant based on mesoporous silica microparticles (MSMPs-Ca10), showing to induce an efficient humoral response and tumor resistance. Mesoporous silica microparticles (MSMPs) offer great advantages as adjuvants: MSMPs possess an adjustable pore size and a biocompatible and biodegradable nature. We know of the great potential of these materials to stimulate antigen presenting cells (APCs), demonstrating to enhance the specific antigenic presentation capacity of human dendritic cells (DCs) to CD8 T cells. DCs are involved in eliciting innate and adaptive responses and can facilitate antigen-specific responses by