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

Falcon-Beas, Cristian; Tittarelli, Andres; Mora-Bau, Gabriela; Tempio, Fabian; Perez, Claudio; Hevia, Daniel; Behrens, Carolina; Flores, Ivan; Falcon-Beas, Felipe; Garrido, Paola; Ascui, Gabriel; Pereda, Cristian; Gonzalez, Fermin E.; Salazar-Onfray, Flavio; Lopez, Mercedes N.

Abstract

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-1 beta and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-beta). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4(+) T cell proliferation and cytokine release (IFN gamma, TNF-alpha 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.

Más información

Título según WOS: Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions
Título según SCOPUS: Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions
Título de la Revista: IMMUNOBIOLOGY
Volumen: 224
Número: 5
Editorial: ELSEVIER GMBH, URBAN & FISCHER VERLAG
Fecha de publicación: 2019
Página de inicio: 697
Página final: 705
Idioma: English
DOI:

10.1016/j.imbio.2019.05.011

Notas: ISI, SCOPUS