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

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

24 January 2024 | 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 & Menna R. Clatworthy
Tumour-retained activated CCR7+ dendritic cells (DCs) are heterogeneous and regulate local anti-tumour cytolytic activity. This study investigates the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses using a photoconvertible mouse model and single-cell RNA sequencing (scRNA-seq). The findings reveal that CCR7+ DCs are the dominant population migrating to tumour-draining lymph nodes (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 become increasingly "exhausted" with prolonged tumour dwell-time. They co-localise with PD-1+ CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules such as OX40L, thereby enhancing anti-tumour cytolytic activity. These data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells. Dendritic cells (DCs) capture tumour antigens and upregulate the chemokine receptor CCR7, which directs their migration to secondary lymphoid organs where they present antigens to T cells. Two major conventional DC (cDC) subsets have been identified in tumours; cDC1 that specialise in cross-presenting tumour antigens to CD8+ T cells and are associated with improved survival, and cDC2 that present exogenous antigens to CD4+ T cells and have variable associations with cancer prognosis and treatment responses. The recent application of single-cell technologies to tissue samples has enabled the distinction of an activated DC state that may arise from both cDC1 and cDC2 but demonstrates a conserved phenotype and transcriptional programme characterised by the expression of LAMP3, genes consistent with a maturation and migration (CCR7, FSCN1, CD40), and immunoregulatory molecules including PD-L1 and PD-L2. This DC population has been variously labelled as "migratory DCs", "mature DCs enriched in immunoregulatory molecules" (mRegDCs), as well as "LAMP3+ DCs". "mature DCs", or "activated DCs". Regardless of nomenclature, single-cell atlasing efforts have identified activated CCR7+ DCs in multiple human cancer types, and the acquisition of this maturation programme appears dependent on the uptake of tumour antigens. Intriguingly, despite the conserved expression of co-inhibitory molecules such as PD-L1 in CCR7+ DCs, the expression of the DC activation-associated marker LAMP3 is associated with improved prognosis in breast, lungTumour-retained activated CCR7+ dendritic cells (DCs) are heterogeneous and regulate local anti-tumour cytolytic activity. This study investigates the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses using a photoconvertible mouse model and single-cell RNA sequencing (scRNA-seq). The findings reveal that CCR7+ DCs are the dominant population migrating to tumour-draining lymph nodes (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 become increasingly "exhausted" with prolonged tumour dwell-time. They co-localise with PD-1+ CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules such as OX40L, thereby enhancing anti-tumour cytolytic activity. These data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells. Dendritic cells (DCs) capture tumour antigens and upregulate the chemokine receptor CCR7, which directs their migration to secondary lymphoid organs where they present antigens to T cells. Two major conventional DC (cDC) subsets have been identified in tumours; cDC1 that specialise in cross-presenting tumour antigens to CD8+ T cells and are associated with improved survival, and cDC2 that present exogenous antigens to CD4+ T cells and have variable associations with cancer prognosis and treatment responses. The recent application of single-cell technologies to tissue samples has enabled the distinction of an activated DC state that may arise from both cDC1 and cDC2 but demonstrates a conserved phenotype and transcriptional programme characterised by the expression of LAMP3, genes consistent with a maturation and migration (CCR7, FSCN1, CD40), and immunoregulatory molecules including PD-L1 and PD-L2. This DC population has been variously labelled as "migratory DCs", "mature DCs enriched in immunoregulatory molecules" (mRegDCs), as well as "LAMP3+ DCs". "mature DCs", or "activated DCs". Regardless of nomenclature, single-cell atlasing efforts have identified activated CCR7+ DCs in multiple human cancer types, and the acquisition of this maturation programme appears dependent on the uptake of tumour antigens. Intriguingly, despite the conserved expression of co-inhibitory molecules such as PD-L1 in CCR7+ DCs, the expression of the DC activation-associated marker LAMP3 is associated with improved prognosis in breast, lung
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[slides] Tumour-retained activated CCR7%2B dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity | StudySpace