Description

The tumor microenvironment harbors ontogenically distinct dendritic cell populations with opposing effects on tumor immunity

Damya Laoui^1,2,*, Jiri Keirsse^1,2,*, Yannick Morias^1,2, Eva Van Overmeire^1,2, Xenia Geeraerts^1,2, Yvon Elkrim^1,2, Mate Kiss^1,2, Evangelia Bolli^1,2, Qods Lahmar^1,2, Dorine Sichien^3,4, Jens Serneels^5,6, Charlotte L. Scott^3,4, Patrick De Baetselier^1,2, Massimiliano Mazzone^5,6, Martin Guilliams^3,4,$, Jo A. Van Ginderachter^1,2,$

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.