Contextual control of CD8+ T cell priming by dendritic cell subsets in tumor and inflammatory microenvironments

Conventional dendritic cells orchestrate adaptive immunity by trafficking peripheral antigens to draining lymph nodes and presenting peptide-MHC complexes to prime naive T cells. Migratory and lymph node resident conventional dendritic cell subsets occupy distinct anatomical niches and have been shown to shape T cell activation in a variety of immunologic contexts including infection, vaccination and cancer. How peripheral tissue context and dendritic cell subset specific transcriptional programs collaborate to determine CD8+ T cell priming remains incompletely defined. Using fluorescent antigen, we tracked antigen distribution, dendritic cell transcriptional programming, and functional cross-presentation across tumor, inflammatory, and steady state tissue contexts. We find that skin tumor antigen is more widely distributed amongst draining lymph node conventional dendritic cells than skin antigen derived from either steady state or inflamed skin tissue. Comparing across dendritic cell subsets, migratory type 1 dendritic cells display higher expression of MHCI antigen presentation machinery and genes associated with cross-presentation compared with lymph node resident type 1 dendritic cells in tumor and inflamed tissue contexts. Similarly, they exhibited superior per-cell cross-presentation and stronger induction of naive CD8+ T cell responses. We find that both antigen access in the lymph node and cell-intrinsic cross-presentation efficiency together predict the magnitude and quality of CD8+ T cell priming regardless of tissue context. These results identify migratory dendritic cells, particularly type 1, as central mediators of antitumor CD8+ T cell responses and support therapeutic strategies that either restrict antigen dispersal from migratory dendritic cells or augment the efficiency of resident dendritic cell cross-presentation. SYNOPSISAntigen transfer from migratory to resident conventional dendritic cell subsets is increased in melanoma compared to steady state or inflamed skin draining lymph nodes. Superior T cell proliferation and expression of cross-presentation machinery by migratory dendritic cells following antigen uptake of tumor suggests retaining antigen within these dendritic cell subsets may improve antitumor CD8+ T cell responses.