Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions

• Published in: Immunobiology (1979) Vol. 224; no. 5; pp. 697 - 705
• Main Authors: Falcón-Beas, Cristián, Tittarelli, Andrés, Mora-Bau, Gabriela, Tempio, Fabián, Pérez, Claudio, Hevia, Daniel, Behrens, Carolina, Flores, Iván, Falcón-Beas, Felipe, Garrido, Paola, Ascui, Gabriel, Pereda, Cristián, González, Fermín E., Salazar-Onfray, Flavio, López, Mercedes N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier GmbH 01.09.2019
• Subjects: Animals; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens, Neoplasm - immunology; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dexamethasone; Dexamethasone - pharmacology; Humans; Immune Tolerance; Immunomodulation; Immunophenotyping; Lymphocyte Activation - immunology; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Melanoma; Mice; Phenotype; Regulatory T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tolerance; Tolerance; Dexamethasone; Dendritic cells; Regulatory T cells; Melanoma
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2019.05.011

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. The effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined. Dexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1β and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-β). 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. 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.