Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific (original) (raw)

The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14 + DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies. NAtURE IMMUNOlOGy | www.nature.com/natureimmunology ResouRce NATuRe ImmuNOLOgy tumor cells and fibroblasts (Supplementary Fig. 1a). We used a panel of lineage markers (Lin) to exclude CD3 + T cells, CD19 + B cells and CD56 + cells (Supplementary Fig. 1a). We analyzed expression of the co-receptor CD14 independently of the lineage channel to efficiently identify CD14 + DCs, which have been reported in patients with cancer 20,21,30-32. Among Lincells, we next gated on CD11c + HLA-DR hi cells to exclude CD11c + HLA-DR neg-lo myeloidderived suppressor cells 33. HLA-DR + CD123 + pDCs were identified in the CD11cgate (Supplementary Fig. 1a). In the Lin-CD45 + gate, we identified four distinct CD11c + cell populations defined by their expression of the antigen-presenting molecule CD1c and CD14 (Fig. 1a). On the basis of published standardized nomenclature for blood DC subsets 34 , CD1c + CD14cells matched the definition of cDC2s, the CD1c-CD14cell population included cDC1s, and CD1c-CD14 + cells were monocytes-macrophages (called 'MonoMacs' here) (Fig. 1a). We also identified a CD1c + CD14 + cell population that co-expressed markers of monocytes and macrophages, such as CD14, CD64 and CD163, and cDC2 markers, such as CD1c, CD206 and Fcε RI (Fig. 1b and Supplementary Fig. 1b). Because these CD1c + CD14 + cells were phenotypically distinct from MonoMacs, and because they had not been systematically distinguished in published studies 34 , we call them 'CD14 + DCs' here. CD56 + CD14 + cells were reported to be interferon-producing killer DCs in the context of cancer 35