Depletion of Conventional Type-1 Dendritic Cells in Established Tumors Suppresses Immunotherapy Efficacy
Alvaro Teijeira 1 2 3 , Saray Garasa 1 2 , Carlos Luri-Rey 1 , Carlos de Andrea 2 4 , Maria Gato 1 , Carmen Molina 1 , Tsuneyasu Kaisho 5 , Assunta Cirella 1 , Arantza Azpilikueta 1 2 3 , Steffanie K Wculek 6 , Josune Egea 1 , Irene Olivera 1 , Inmaculada Rodriguez 1 2 3 , Ana Rouzaut 1 2 , Vladislav Verkusha 7 , Karmele Valencia 2 3 8 , David Sancho 6 , Pedro Berraondo 1 2 3 , Ignacio Melero 1 2 3 9
The ability of conventional type-1 dendritic cells (cDC1) to cross-present tumor antigens to CD8+ T cells is critical for the induction of antitumor CTLs. Mice that are constitutively deficient in cDC1 cells have been reported to fail to respond to immunotherapy strategies based on checkpoint inhibitors.
However, further work is needed to clarify the precise time during immunotherapy treatment that cDC1 cells are required for the beneficial effect of treatment. Here, we used a refined XCR1-DTR-Venus transgenic mouse model to acutely deplete cDC1 cells and trace their behavior using intravital microscopy. Diphtheria toxin-mediated cDC1 depletion prior to immunotherapy treatment with anti-PD-1 and/or anti-CD137 immunostimulatory mAbs completely ablated antitumor efficacy.
The efficacy of adoptive T-cell therapy was also hampered by prior cDC1 depletion.
After the onset of immunotherapy treatment, depletion of cDC1s only moderately reduced the therapeutic efficacy of anti-PD-1 and anti-CD137 mAbs. Intravital microscopy of liver-engrafted tumors revealed changes in the intratumoral behavior of cDC1 cells in mice receiving immunotherapy, and treatment with diphtheria toxin to deplete cDC1s impaired tumor T-cell infiltration and function.
These results reveal that the functional integrity of the cDC1 compartment is required at the onset of various immunotherapies to successfully treat established tumors.
Significance: These findings reveal the intratumoral behavior of cDC1 dendritic cells in transgenic mouse models and demonstrate that the efficacy of immunotherapy regimens is precluded by elimination of these cells.