Teijeira et al. used XCR1-DTR-Venus transgenic mice that express traceable Venus in cDC1 cells (which can be acutely depleted with diphtheria toxin) to interrogate when cDC1s are required relative to anti-PD-1 and anti-CD137 therapies. cDC1 depletion prior to immunotherapy treatment completely prevented antitumor efficacy while depletion after immunotherapy onset was only partially inhibitory. Adoptive T cell therapy was also negatively affected by prior cDC1 depletion. Intravital microscopy of metastatic liver tumors revealed impaired T cell infiltration and function (increased exhaustion) after depleting cDC1 cells, identifying an important role for ongoing cDC1–T cell cross-talk.
Contributed by Katherine Turner
ABSTRACT: 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 cytotoxic T lymphocytes. 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 monoclonal antibodies (mAbs) completely ablated anti-tumor 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.
Author Info: (1) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain. (2) University of Navarra, Pamplona, Spain. (3) University of Nava
Author Info: (1) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain. (2) University of Navarra, Pamplona, Spain. (3) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain. (4) University of Navarra, Pamplona, Navarra, Spain. (5) Fundacion Miguel Servet, Spain. (6) University of Navarra, Pamplona, Spain. (7) Wakayama Medical University, Wakayama, Japan. (8) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain. (9) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain. (10) CNIC, Madrid, Spain. (11) University of Navarra, Center for Applied Medical Research (CIMA), Centro de Investigaciðn Biomðdica en Red de Enfermedades Hepðticas y Digestivas (CIBEREHD) and IdiSNA, Instituto de Investigaciðn Sanitaria de Navarra, Pamplona, Navarra, Spain. (12) CIMA+ (Canada), Pamplona, Navarra, Spain. (13) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. (14) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. (15) Albert Einstein College of Medicine, Bronx, United States. (16) Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. (17) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (18) Cima Universidad de Navarra, Pamplona, Navarra, Spain. (19) University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Navarra, Spain.
