Frontiers in Immunology (Oct 2022)

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

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

DOI
https://doi.org/10.3389/fimmu.2022.991311
Journal volume & issue
Vol. 13

Abstract

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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