RESUMEN
Ovarian epithelial carcinoma (OEC) is the most frequent ovarian tumor, characterized by a high mortality in advanced stages where conventional therapies are not effective. Based on the role of the immune system in the progression of this disease, immunotherapy using checkpoint blockade has been considered as a therapeutic alternative. Nevertheless, its results do not match up to the positive results in entities like melanoma and other malignancies, suggesting the need to find other therapies to be used alone or in combination. Dendritic cell- (DC-) based vaccines have shown promising results in several types of cancer, such as melanoma, prostate, and lung cancers, due to the essential role played by DCs in the activation of specific T cells, thus using other ways of activating the immune response than immune checkpoint blockade. During the last decade, we have used DC-based vaccines loaded with an allogeneic heat shock-conditioned melanoma cell lysate in the treatment of advanced stage patients in a series of clinical trials. In these studies, 60% of treated patients showed immunological responses which correlated positively with improved survival. Considering the relevance of ovarian cancer and the promising results of our DC-based vaccine, we show here that heat shock-conditioned cell lysates derived from ovarian epithelial carcinoma cell lines have the potential to induce the phenotypic and functional maturation of human DC, which in turn, is able to induce an efficient CD4+ and CD8+ T cell-mediated immune responses against ovarian cancer cell lines in vitro. In summary, OEC heat shock-conditioned cell lysate-loaded DCs may be considered for future combined immunotherapy approaches against ovarian tumors.
Asunto(s)
Carcinoma Epitelial de Ovario/inmunología , Células Dendríticas/inmunología , Respuesta al Choque Térmico , Neoplasias Ováricas/inmunología , Linfocitos T/inmunología , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/terapia , Línea Celular Tumoral , Células Dendríticas/metabolismo , Femenino , Respuesta al Choque Térmico/genética , Respuesta al Choque Térmico/inmunología , Humanos , Inmunoterapia , Interferón gamma/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/terapia , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Dendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses. METHODS: The effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined. RESULTS: Dexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1ß and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-ß). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4+ T cell proliferation and cytokine release (IFNγ, TNF-α and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity. CONCLUSIONS: These findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.
Asunto(s)
Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Antígenos de Neoplasias/inmunología , Células Dendríticas/inmunología , Dexametasona/farmacología , Tolerancia Inmunológica , Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Humanos , Inmunomodulación , Inmunofenotipificación , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/metabolismoRESUMEN
Autologous dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are a promising immunological tool for cancer therapy. These stimulate the antitumor response and immunological memory generation. Nevertheless, many patients remain refractory to DC approaches. Antigen (Ag) delivery to DCs is relevant to vaccine success, and antigen peptides, tumor-associated proteins, tumor cells, autologous tumor lysates, and tumor-derived mRNA have been tested as Ag sources. Recently, DCs loaded with allogeneic tumor cell lysates were used to induce a potent immunological response. This strategy provides a reproducible pool of almost all potential Ags suitable for patient use, independent of MHC haplotypes or autologous tumor tissue availability. However, optimizing autologous tumor cell lysate preparation is crucial to enhancing efficacy. This review considers the role of cancer cell-derived lysates as a relevant source of antigens and as an activating factor for ex vivo therapeutic DCs capable of responding to neoplastic cells. These promising therapies are associated with the prolonged survival of advanced cancer patients.