• CAR T-cell
• dendritic cell
• FLT3L
• GD2
• IL-12
• lung cancer

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of haematological malignancies, but its efficacy continues to be limited in solid tumours. Our group has recently developed a novel preclinical platform based on DC progenitors (DCPs), which are engineered to express two immunostimulatory cytokines: interleukin 12 (IL-12) and Fms-related tyrosine kinase 3 ligand (FLT3L). Termed cytokine-armed DCPs, our approach differs from traditional dendritic cell (DC)-vaccines by eliminating the need for ex vivo antigen loading.
Cytokine-armed DCPs generate type I conventional DCs (cDC1) upon transfer to tumour-bearing mice and display greater anti-tumour effects than mo-DCs in several mouse tumour models. Notably, we have already demonstrated that these engineered cells synergized with CAR-T cell therapy in a glioma model. Encouraged by these promising results, we investigated whether cytokine-armed DCPs could similarly enhance the therapeutic efficacy of GD2 CAR-T cells in a murine orthotopic lung adenocarcinoma model.
Our results demonstrate that while GD2 CAR-T cells exhibit antigen-specific cytotoxicity both in vitro and in vivo, their anti-tumour efficacy is limited as monotherapy. Conversely, DCP monotherapy activated the endogenous immune compartment but displayed modest tumour control. Using longitudinal micro-CT imaging, we showed that the combination of DCPs and CAR-T cells achieved near-complete tumour regression in several treated mice. Flow-cytometry analysis revealed that this combination therapy enhanced CAR-T cell persistence, reduced regulatory T-cell infiltration, promoted M1 macrophage polarization, and activate cytotoxic endogenous T-cells. As a potential resistant mechanism to the combination therapy, we observed a downregulation of GD2 expression in cancer cells, as demonstrated by immunofluorescence analysis.
These findings suggest that DCPs can unleash the potential of CAR-T cell therapy in lung adenocarcinoma and provide an initial analysis of the tumour microenvironment modifications underlying their efficacy.