CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
表达 DNASE1L3 的树突状细胞通过降解中性粒细胞胞外诱捕网促进 CD8(+) T 细胞功能和抗 PD-(L)1 治疗疗效
英文原题：DNASE1L3-expressing dendritic cells promote CD8(+) T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps.
查看英文原题
DNASE1L3-expressing dendritic cells promote CD8(+) T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps.
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中文摘要
CD8 + T 细胞在肿瘤微环境（TME）中的排斥和功能障碍是抗 PD-(L)1 治疗最具挑战性的障碍之一。在此，我们报道肿瘤浸润树突状细胞（DC）特异性表达的脱氧核糖核酸酶 DNASE1L3 与癌症患者抗 PD-(L)1 治疗的良好结局呈正相关。DC 中 DNASE1L3 条件性敲除会导致肿瘤生长增强，并通过损害 CD8 + T 细胞的浸润和效应功能削弱抗 PD-L1 治疗疗效。相反，注射 DNASE1L3 可促进 CD8 + T 细胞浸润并减少 TME 中的耗竭，显著延缓肿瘤生长并增强抗 PD-L1 应答。DNASE1L3 + DC 可降解抑制肿瘤中 CD8 + T 细胞空间分布的中性粒细胞胞外诱捕网，从而在人类癌症中促成细胞毒性 CD8 + T 细胞枢纽的建立。
我们的发现揭示了 DC 在调节瘤内 CD8 + T 细胞中的作用，并确定 DNASE1L3 是改善抗 PD-(L)1 治疗的一个有前景的靶点。
展开英文摘要原文
CD8 + T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy.
Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8 + T cells.
Conversely, injection with DNASE1L3 promotes CD8 + T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3 + DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8 + T cells in tumors, enabling establishment of cytotoxic CD8 + T cell hubs in human cancers.
Our findings reveal a role of DC in regulating intratumoral CD8 + T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.
论文信息
- 作者
- Chen D、Jin Z、Chu H、Wu Y、Bian Y、Yuan T、Lv H、Xia Q
- 第一作者单位
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China.China
- 通讯作者单位
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China; Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing 400016, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: bo.zhu@tmmu.edu.cn.China
- 期刊
- Cancer cell2025 Sep 8
- 原文标识
- PubMed 40816293 · DOI 10.1016/j.ccell.2025.07.014