Single-cell transcriptomics reveal distinct subsets of activated dendritic cells in the tumor microenvironment

Dendritic cells (DCs) are rare in tumors where their heterogeneity remains unclear. To overcome the limitations of surface marker-based analyses, we utilized DC-reporter mice (Zbtb46GFP/+) to isolate tissue and tumor DCs and performed single-cell RNA sequencing (scRNA-seq). The known DC subsets were conserved across tissues, albeit at different frequencies. Activated and mature DCs formed a distinct cluster in both healthy and tumor tissues and displayed the hallmark DC migratory program (migratory DCs). We also identified a distinct subset of activated DCs in tumors that did not induce the migratory program, instead displaying signatures of interferon exposure (interferon-DCs or IFN-DCs). IFN-DCs were proficient in antigen-presentation, supported T cell proliferation, and expressed high levels of T cell-attracting chemokines. IFN-DCs further comprised of IFN1- and IFN2-DCs that were generated from CD11b+ DCs in response to type I or type II interferons respectively. We also identified IFN-DCs in scRNA-seq of human tumor-infiltrating leukocytes. These findings illustrate DC heterogeneity in tumors and suggest the existence of an interferon regulated division of labor among activated DCs whereby the migratory DCs drive T cell priming in draining lymph nodes while the sessile IFN-DCs help recruit T cells and regulate their function in the tumor microenvironment. One Sentence SummaryTumors harbor an interferon-regulated activated sessile subset of dendritic cells.