Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity

Colin Y. C. Lee, Bethany C. Kennedy, Nathan Richoz, Isaac Dean, Zewen K. Tuong, Fabrina Gaspal, Zhi Li, Claire Willis, Tetsuo Hasegawa, Sarah K. Whiteside, David A. Posner, Gianluca Carlesso, Scott A. Hammond, Simon J. Dovedi, Rahul Roychoudhuri, David R. Withers () and Menna R. Clatworthy ()
Additional contact information
Colin Y. C. Lee: University of Cambridge
Bethany C. Kennedy: University of Birmingham
Nathan Richoz: University of Cambridge
Isaac Dean: University of Birmingham
Zewen K. Tuong: University of Cambridge
Fabrina Gaspal: University of Birmingham
Zhi Li: University of Birmingham
Claire Willis: University of Birmingham
Tetsuo Hasegawa: University of Cambridge
Sarah K. Whiteside: University of Cambridge
David A. Posner: University of Cambridge
Gianluca Carlesso: AstraZeneca
Scott A. Hammond: AstraZeneca
Simon J. Dovedi: AstraZeneca
Rahul Roychoudhuri: University of Cambridge
David R. Withers: University of Birmingham
Menna R. Clatworthy: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44787-1

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