Lee et al. showed that CCR7+ DCs are transcriptionally heterogeneous populations, consisting of a subset that migrates to dLNs and a subset that resides in the tumor despite CCR7 expression, with the capacities to support or inhibit the cytotoxic T cell niche. Tumor-retained CCR7+ DCs acquired transcriptional features consistent with exhaustion, and co-localized with PD-1+ CD8+ T cells in human and murine solid tumors. Anti-PD-L1 treatment enhanced the expression of T cell-stimulatory molecules, promoted immunogenic CCR7+ DC–CD8+ T cell interactions, and augmented antitumor cytolytic activity, which was conserved across human cancers.
Contributed by Shishir Pant
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.
Author Info: (1) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. Cellular Genetics, Wellcome S
Author Info: (1) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. (2) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. (3) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. (4) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. (5) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. (6) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. (7) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. (8) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. (9) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. (10) Department of Pathology, University of Cambridge, Cambridge, UK. (11) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. (12) Early Oncology R&D, AstraZeneca, Gaithersburg, MD, USA. (13) Early Oncology R&D, AstraZeneca, Gaithersburg, MD, USA. (14) Early Oncology R&D, AstraZeneca, Cambridge, UK. (15) Department of Pathology, University of Cambridge, Cambridge, UK. (16) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. d.withers@bham.ac.uk. (17) Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK. mrc38@medschl.cam.ac.uk. Cellular Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. mrc38@medschl.cam.ac.uk.
