"Examining dendritic cell heterogeneity in the tumor microenvironment"

Jerrick To, Samir Devalajara, Ian Folkert, Graham Lobel, Zachary Lanzar and Malay Haldar

Dendritic cells (DCs) are key antigen-presenting cells comprising of functionally and phenotypically distinct subsets. DCs are rare in tumors where their heterogeneity remains unclear. To overcome the limitations of surface marker-based analyses, we utilized genetically engineered DC-reporter mice (Zbtb46-GFP) to isolate tissue and tumor DCs and performed single-cell RNA sequencing (scRNA-seq). Through the scRNA-seq approach, the major ontological DC subsets (CD103+ DC1 and CD11b+ DC2) were identified along with two activated DC subsets. One activated subset displayed a hallmark DC migratory program (migratory DC or mDC) and showed superior T cell stimulatory properties. Notably, tumors also harbored a distinct subset of activated DCs that lack a migratory program, instead displaying signature of interferon exposure (interferon-DCs or IFN-DC). IFN-DCs were proficient in antigen-presentation, supported T cell proliferation, and expressed T cell-recruiting chemokines. Using a combination of genetic, pharmacologic, and computational approaches, we further show that both type I and II interferons can regulate IFN-DCs from DC2s in the tumor microenvironment. Taken together, our findings illuminate DC heterogeneity in tumors and suggest a ‘division of labor’ amongst activated DCs, whereby mDCs migrate to and drive T cell priming in draining lymph nodes while IFN-DCs help recruit T cells and regulate their function within the tumor microenvironment. Finally, analysis of DCs from an aggregated human mononuclear phagocyte scRNA-seq dataset revealed a similar split in migratory or interferon-signaling modules among human tumor DCs.