Journal Article

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

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

2024

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 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. Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/31 / 14/63 / 38/91 / 631/250 / 631/250/2504 / 631/250/2504/133 / 631/250/251 / 631/67/580 / Animals / Anticancer properties / Antigen Presentation / Antigens / CC chemokine receptors / CD8 antigen / CD8-Positive T-Lymphocytes / Cell activation / Cell migration / Cytolytic activity / Cytotoxicity / Dendritic Cells / Dendritic structure / Dwell time / Heterogeneity / Humanities and Social Sciences / Humans / Inflammation / Lymph nodes / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Neoplasms - genetics / Neoplasms - therapy / Ox40L protein / PD-1 protein / PD-L1 protein / Receptors, CCR7 - genetics / Science / Science (multidisciplinary) / Solid tumors / Tumors