Paper

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

Gaspal, Fabrina, Willis, Claire, Whiteside, Sarah K, Dean, Isaac, Li, Zhi, Tuong, Zewen K, Hasegawa, Tetsuo, Lee, Colin YC, Kennedy, Bethany C, Hammond, Scott A, Withers, David R, Richoz, Nathan, Carlesso, Gianluca, Posner, David A, Clatworthy, Menna R, Dovedi, Simon J, Roychoudhuri, Rahul

2023

Overview

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to a maturation programme enriched in regulatory molecule expression, including PD-L1, termed mRegDC. However, the spatio- temporal dynamics and role of mRegDCs in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs were 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. Specifically, they demonstrated a progressive reduction in the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour mRegDCs spatially co-localised with PD-1+CD8+ T cells in human and murine solid tumours. Following anti-PD-L1 treatment, tumour-residing mRegDCs adopted a state enriched in lymphocyte stimulatory molecules, including OX40L, which was capable of augmenting anti- tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in mRegDCs that may underpin a variable capacity to support intratumoural cytotoxic T cells, and provide insights into their role in cancer immunotherapy.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Immunology