The tumor microenvironment harbors ontogenically distinct dendritic cell populations with opposing effects on tumor immunity
Damya Laoui1,2,*, Jiri Keirsse1,2,*, Yannick Morias1,2, Eva Van Overmeire1,2, Xenia Geeraerts1,2, Yvon Elkrim1,2, Mate Kiss1,2, Evangelia Bolli1,2, Qods Lahmar1,2, Dorine Sichien3,4, Jens Serneels5,6, Charlotte L. Scott3,4, Patrick De Baetselier1,2, Massimiliano Mazzone5,6, Martin Guilliams3,4,$, Jo A. Van Ginderachter1,2,$
1Laboratory of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent, Belgium; 2Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; 3Unit of Immunoregulation and mucosal immunology, VIB Inflammation Research Center, Ghent, Belgium; 4Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; 5Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium; 6Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, K.U. Leuven, Belgium; *equal contribution; $ shared senior authorship
Various steady-state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1, cDC2 and monocyte-derived DC, displaying differential functional specializations. The identification of functionally distinct tumor-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumors as well as human tumors harbor ontogenically discrete TADC subsets. Monocyte-derived TADC are prominent in tumor antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADC have lymph node migratory potential, whereby cDC1 efficiently activate CD8+ T cells and cDC2 induce Th17 cells. Mice vaccinated with cDC2 displayed a reduced tumor growth accompanied by a reprogramming of pro-tumoral TAM and a reduction of MDSC, while cDC1 vaccination strongly induces anti-tumor CTL. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.
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