Lee et al. showed that CCR7+ DCs are transcriptionally heterogeneous populations, consisting of a subset that migrates to dLNs and a subset that resides in the tumor despite CCR7 expression, with the capacities to support or inhibit the cytotoxic T cell niche. Tumor-retained CCR7+ DCs acquired transcriptional features consistent with exhaustion, and co-localized with PD-1+ CD8+ T cells in human and murine solid tumors. Anti-PD-L1 treatment enhanced the expression of T cell-stimulatory molecules, promoted immunogenic CCR7+ DC–CD8+ T cell interactions, and augmented antitumor cytolytic activity, which was conserved across human cancers.
Contributed by Shishir Pant
ABSTRACT: Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7(+) DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7(+) DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7(+) DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7(+) DCs co-localise with PD-1(+)CD8(+) T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7(+) DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells.