- [INMUNOLOGÍA E INMUNOTERAPIA]
- [INMUNOMODULACIÓN Y MICROAMBIENTE TUMORAL]
- [DESARROLLO DE VACUNAS]
- [TUMORES SÓLIDOS]
- [BIOMARCADORES Y NUEVAS DIANAS TERAPÉUTICAS EN CÁNCER DE PULMÓN]
Inhibition of adjuvant-induced TAM receptors potentiates cancer vaccine immunogenicity and therapeutic efficacy
Diana Llopiz, Marta Ruiz, Leyre Silva, David Repáraz, Belén Aparicio, Josune Egea, Juan J Lasarte, Esther Redin, Alfonso Calvo, Matthew Angel, Jay A Berzofsky, David Stroncek, Pablo Sarobe
Analyzing immunomodulatory elements operating during antitumor vaccination in prostate cancer patients and murine models we identified IL-10-producing DC as a subset with poorer immunogenicity and clinical efficacy. Inhibitory TAM receptors MER and AXL were upregulated on murine IL-10+ DC. Thus, we analyzed conditions inducing these molecules and the potential benefit of their blockade during vaccination. MER and AXL upregulation was more efficiently induced by a vaccine containing Imiquimod than by a poly(I:C)-containing vaccine.
Interestingly, MER expression was found on monocyte-derived DC, and was dependent on IL-10. TAM blockade improved Imiquimod-induced DC activation in vitro and in vivo, resulting in increased vaccine-induced T-cell responses, which were further reinforced by concomitant IL-10 inhibition. In different tumor models, a triple therapy (including vaccination, TAM inhibition and IL-10 blockade) provided the strongest therapeutic effect, associated with enhanced T-cell immunity and enhanced CD8+ T cell tumor infiltration.
Finally, MER levels in DC used for vaccination in cancer patients correlated with IL-10 expression, showing an inverse association with vaccine-induced clinical response. These results suggest that TAM receptors upregulated during vaccination may constitute an additional target in combinatorial therapeutic vaccination strategies.
CITA DEL ARTÍCULO Cancer Lett. 2021 Feb 28;499:279-289. doi: 10.1016/j.canlet.2020.11.022.