Publicaciones científicas

Gemcitabine-mediated depletion of immunosuppressive dendritic cells enhances the efficacy of therapeutic vaccination

14-oct-2022 | Revista: Frontiers in Immunology

David Repáraz 1 2 3, Marta Ruiz 1 2 3, Leyre Silva 1 2 3, Belén Aparicio 1 2 3, Josune Egea 1 2 3, Elizabeth Guruceaga 1 2, Daniel Ajona 1 2 4 5, Yaiza Senent 1 2 4, Enrique Conde 1 2, Flor Navarro 1, Sergio Barace 1, Diego Alignani 1 2, Sandra Hervás-Stubbs 1 2 3, Juan José Lasarte 1 2, Diana Llopiz 1 2 3, Pablo Sarobe 1 2 3


Abstract

Vaccination using optimized strategies may increase response rates to immune checkpoint inhibitors (ICI) in some tumors. To enhance vaccine potency and improve thus responses to ICI, we analyzed the gene expression profile of an immunosuppressive dendritic cell (DC) population induced during vaccination, with the goal of identifying druggable inhibitory mechanisms. RNAseq studies revealed targetable genes, but their inhibition did not result in improved vaccines. However, we proved that immunosuppressive DC had a monocytic origin.

Thus, monocyte depletion by gemcitabine administration reduced the generation of these DC and increased vaccine-induced immunity, which rejected about 20% of LLC-OVA and B16-OVA tumors, which are non-responders to anti-PD-1. This improved efficacy was associated with higher tumor T-cell infiltration and overexpression of PD-1/PD-L1.

Therefore, the combination of vaccine + gemcitabine with anti-PD-1 was superior to anti-PD-1 monotherapy in both models. B16-OVA tumors benefited from a synergistic effect, reaching 75% of tumor rejection, but higher levels of exhausted T-cells in LLC-OVA tumors co-expressing PD-1, LAG3 and TIM3 precluded similar levels of efficacy.

Our results indicate that gemcitabine is a suitable combination therapy with vaccines aimed at enhancing PD-1 therapies by targeting vaccine-induced immunosuppressive DC.

Keywords: anti-PD-1; antitumor therapeutic vaccination; gemcitabine; immunosuppressive DC; monocyte depletion.

CITA DEL ARTÍCULO  Front Immunol. 2022 Oct 10:13:991311. doi: 10.3389/fimmu.2022.991311. eCollection 2022.

Nuestros autores

David Repáraz Pernaut
Dra. Marta Ruiz Egozcue
Técnico de Investigación Grupo de Investigación en Péptidos
Leyre Silva Vergara
Belén Aparicio de la Torre
Dra. Josune Orbe Lopategui
Elizabet Guruceaga Martínez
Técnico de Investigación Bioinformático Plataforma Bioinformática
Dr. Daniel Ajona Martínez-Polo
Yaiza Senent Valero
Enrique Conde Gallastegi
Sergio Barace Jiménez
Diego Alignani
Técnico de laboratorio Plataforma de Citometría
Dra. Sandra Hervás Stubbs
Investigadora | Investigadora principal Programa de Investigación de Inmunología e Inmunoterapia
Dra. Diana Llópiz Khatchikian