Time-, tissue- and treatment-associated heterogeneity in tumour-residing migratory DCs

Abstract

CCR7-expressing mature DCs enriched in immunoregulatory molecules (mRegDCs), such as PD-L1, have been identified in tumours and draining lymph nodes (dLN), but their spatiotemporal dynamics and role in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs comprised the dominant DC population arriving in the dLN, but a subset remained tumour-resident despite CCR7 expression. These tumour-retained mRegDCs were phenotypically and transcriptionally distinct from their dLN counterparts and were heterogeneous, with increasing features of an 'exhausted' transcriptional profile with more prolonged tumour residence. This was characterised by reduced expression of antigen presentation and pro-inflammatory transcripts, and these 'exhaustion' features were attenuated by anti-PD-L1 treatment. Tumour mRegDCs spatially co-localised with effector CD8+ T cells in human solid tumours, and anti-PD-L1 treatment enhanced their expression of several T cell-stimulatory molecules. Altogether, these data provide fundamental insights into mRegDC biology and their role in cancer immunotherapy.