Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y. Wan, Qi-Jing Li, Bo Zhu
{"title":"表达dnase1l3的树突状细胞通过降解中性粒细胞胞外陷阱促进CD8+ T细胞功能和抗pd -(L)1治疗效果","authors":"Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y. Wan, Qi-Jing Li, Bo Zhu","doi":"10.1016/j.ccell.2025.07.014","DOIUrl":null,"url":null,"abstract":"CD8<sup>+</sup> 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<sup>+</sup> T cells. Conversely, injection with DNASE1L3 promotes CD8<sup>+</sup> T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3<sup>+</sup> DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8<sup>+</sup> T cells in tumors, enabling establishment of cytotoxic CD8<sup>+</sup> T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8<sup>+</sup> T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"22 1","pages":""},"PeriodicalIF":44.5000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps\",\"authors\":\"Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y. Wan, Qi-Jing Li, Bo Zhu\",\"doi\":\"10.1016/j.ccell.2025.07.014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"CD8<sup>+</sup> 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<sup>+</sup> T cells. Conversely, injection with DNASE1L3 promotes CD8<sup>+</sup> T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3<sup>+</sup> DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8<sup>+</sup> T cells in tumors, enabling establishment of cytotoxic CD8<sup>+</sup> T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8<sup>+</sup> T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.\",\"PeriodicalId\":9670,\"journal\":{\"name\":\"Cancer Cell\",\"volume\":\"22 1\",\"pages\":\"\"},\"PeriodicalIF\":44.5000,\"publicationDate\":\"2025-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ccell.2025.07.014\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2025.07.014","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps
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.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.