Projects per year
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.
Original language | English |
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Article number | 682 |
Number of pages | 18 |
Journal | Nature Communications |
Volume | 15 |
Issue number | 1 |
DOIs | |
Publication status | Published - 24 Jan 2024 |
Bibliographical note
Acknowledgments:CYCL is funded by the Gates Cambridge scholarship trust and University of Cambridge School of Clinical Medicine Elmore fund. BCK was supported by Cancer Research UK (SEBSTF-2021/100002). ID was supported by an iCASE Studentship with AstraZeneca. DRW was funded by Cancer Research UK Immunology Project Award C54019/A27535, Cancer Research Institute CLIP grant CRI3128, Worldwide Cancer Research Grant 21-0073 and a Medical Research Council IMPACT iCASE Studentship with AstraZeneca. MRC is supported by the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Blood and Transplant Research Unit and a Wellcome Investigator Award (220268/Z/20/Z). We thank A. Ptasinska and other members of Genomics Birmingham at University of Birmingham for their help with single-cell RNA-sequencing experiments, and the University of Birmingham Flow Cytometry Facility. We thank Dr. Y. Miwa (Tsukuba University, Tsukuba, Japan) and Dr. O. Kanagawa (RIKEN Research Center for Allergy and Immunology, Yokohama, Japan) and Dr. M. Tomura (Osaka Ohtani University, Tondabayashi, Japan) for the Kaede mice. We thank the Mary Lyon Centre at MRC Harwell for OX40L reporter mice used in this study (award MC_UP_2201/2). We thank Marina Botto (Imperial College London) for the OX40Lfl/fl mice. Icons in Figs. 1a, 5d and g were created with BioRender.com.
Copyright:
© 2024. The Author(s).
Keywords
- Humans
- Animals
- Mice
- CD8-Positive T-Lymphocytes
- Receptors, CCR7/genetics
- Neoplasms/genetics
- Antigen Presentation
- Dendritic Cells
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Dive into the research topics of 'Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity'. Together they form a unique fingerprint.Projects
- 3 Finished
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Determining the source and nature of checkpoint blockade sensitive anti-tumour T cells
Withers, D. (Principal Investigator)
1/05/21 → 31/07/23
Project: Research
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Investigating the dynamics of anti-tumour immune responses to optimise immune checkpoint blockade
Withers, D. (Principal Investigator)
1/09/20 → 31/08/22
Project: Research
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Revealing anti-tumour T cell recruitment and recirculation in vivo to optimise therapeutic intervention.
Withers, D. (Principal Investigator)
1/02/19 → 31/01/22
Project: Research