细胞毒性T细胞
C-C趋化因子受体7型
生物
免疫疗法
CD8型
人口
癌症研究
下调和上调
抗原
抗原呈递
免疫学
癌症免疫疗法
免疫系统
T细胞
医学
趋化因子
基因
遗传学
体外
环境卫生
趋化因子受体
作者
Colin Y.C. Lee,Bethany C. Kennedy,Nathan Richoz,Isaac Dean,Zewen Kelvin 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
标识
DOI:10.1101/2023.07.03.547454
摘要
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 a maturation programme enriched in regulatory molecule expression, including PD-L1, termed mRegDC. However, the spatio- temporal dynamics and role of mRegDCs in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs were the dominant DC population arriving in the dLN, but a subset remained tumour-resident despite CCR7 expression. These tumour-retained mRegDCs were phenotypically and transcriptionally distinct from their dLN counterparts and were heterogeneous. Specifically, they demonstrated a progressive reduction in the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour mRegDCs spatially co-localised with PD-1 + CD8 + T cells in human and murine solid tumours. Following anti-PD-L1 treatment, tumour-residing mRegDCs adopted a state enriched in lymphocyte stimulatory molecules, including OX40L, which was capable of augmenting anti- tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in mRegDCs that may underpin a variable capacity to support intratumoural cytotoxic T cells, and provide insights into their role in cancer immunotherapy.
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