[Dendritic cells in cancer immunotherapy]. / Inmunoterapia genética con células dendríticas para el tratamiento del cáncer.

Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities.

Inmunoterapia genética con células dendríticas para el tratamiento del cáncer / Dendritic cells in cancer immunotherapy

Desde comienzos del siglo XX, los científicos han intentado aprovechar las actividades naturales del sistema inmunológico para curar el cáncer. Sin embargo, las inmunoterapias no han dado el resultado clínico que podría haberse esperado. De hecho, lo tratamientos anti-neoplásicos clásicos como la cirugía, la radioterapia y la quimioterapia siguen consistiendo en la primera línea de tratamiento. Aun así, existe un gran número de evidencias experimentales sobre la inmunogenicidad de las células cancerosas. Sin embargo, la activación efectiva de las respuestas T anti-cancerosas depende estrechamente de la presentación eficiente de antígenos tumorales por parte de células presentadoras de antígeno profesionales, como las células dendríticas (dendritic cells, DC). Aunque se han desarrollado un gran número de estrategias para reforzar las funciones de presentación de antígeno de las DC, la inmunoterapia como tratamiento anti-neoplásico todavía no es tan efectiva como esperaríamos de acuerdo con los resultados obtenidos en modelos preclínicos durante las últimas décadas. En este trabajo no pretendemos revisar exhaustivamente la inmunoterapia con DC, un campo ampliamente extenso y tratado en otras revisiones especializadas. Aquí se exponen la experiencias que nuestro grupo ha llevado a cabo durante la última década modificando genéticamente a las DC para mejorar su eficacia anti-tumoral (AU)

Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their antitumour capacities (AU)

Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells.

The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the multifunctional status of T cells are a key for immunotherapy. Dendritic cells (DCs) are professional antigen presenting cells that regulate T-cell functions by providing positive and negative co-stimulatory signals. A key negative regulator of T-cell activity is provided by binding of programmed death-1 (PD-1) receptor on activated T cells, to its ligand PD-L1, expressed on DCs. We investigated the impact of interfering with PD-L1/PD-1 co-stimulation on the multifunctionality of T cells, by expression of the soluble extracellular part of PD-1 (sPD-1) or PD-L1 (sPD-L1) in human monocyte-derived DCs during antigen presentation. Expression, secretion and binding of these soluble molecules after mRNA electroporation were demonstrated. Modification of DCs with sPD-1 or sPD-L1 mRNA resulted in increased levels of the co-stimulatory molecule CD80 and a distinct cytokine profile, characterized by the secretion of IL-10 and TNF-α, respectively. Co-expression in DCs of sPD-1 and sPD-L1 with influenza virus nuclear protein 1 (Flu NP1) stimulated Flu NP1 memory T cells, with a significantly higher number of multifunctional T cells and increased cytokine secretion, while it did not induce regulatory T cells. These data provide a rationale for the inclusion of interfering sPD-1 or sPD-L1 in DC-based immunotherapeutic strategies.