OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment

doi:10.7150/thno.83495

KMS > 免疫化学研究所

	OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment
	Liu, Shiyu 1,2,3; Li, Fan 1,2,3; Ma, Qiongqiong 1,2,3; Du, Mingjuan4 ; Wang, Haoran 1,2; Zhu, Yiping 1,2,3; Deng, Li 3; Gao, Wenrui 3; Wang, Chunlei 1,2,3; Liu, Yanqin 1,2,3; Zhao, Zhuoqian 1,2; Liu, Huanzhen4 ; Wang, Ruikun 1,2; Tian, Yujie 1,2,3; Hu, Manli4 ; Wan, Yajuan 1,2; Lu, Wenyi 5; Zhang, Meng 5; Zhao, Mingfeng 5; Cao, Youjia 1,2; Zhang, Hongkai 1,2,3; Wang, Wei4 ; Wang, Hui 3; Wang, Yuan 1,2,3
	2023
发表期刊	THERANOSTICS
ISSN	1838-7640
卷号	13 期号:12
发表状态	已发表
DOI	10.7150/thno.83495
摘要	Rationale:The resistance of pancreatic ductal adenocarcinoma (PDAC) to immunotherapies is caused by the immunosuppressive tumor microenvironment (TME) and dense extracellular matrix. Currently, the efficacy of an isolated strategy targeting stromal desmoplasia or immune cells has been met with limited success in the treatment of pancreatic cancer. Oncolytic virus (OV) therapy can remodel the TME and damage tumor cells either by directly killing them or by enhancing the anti-tumor immune response, which holds promise for the treatment of PDAC. This study aimed to investigate the therapeutic effect of OX40L-armed OV on PDAC and to elucidate the underlying mechanisms. Methods:Murine OX40L was inserted into herpes simplex virus-1 (HSV-1) to construct OV-mOX40L. Its expression and function were assessed using reporter cells, cytopathic effect, and immunogenic cell death assays. The efficacy of OV-mOX40L was then evaluated in a KPC syngeneic mouse model. Tumor-infiltrating immune and stromal cells were analyzed using flow cytometry and single-cell RNA sequencing to gain insight into the mechanisms of oncolytic virotherapy. Results:OV-mOX40L treatment delayed tumor growth in KPC tumor-bearing C57BL/6 mice. It also boosted the tumor-infiltrating CD4+ T cell response, mitigated cytotoxic T lymphocyte (CTL) exhaustion, and reduced the number of regulatory T cells. The treatment of OV-mOX40L reprogrammed macrophages and neutrophils to a more pro-inflammatory anti-tumor state. In addition, the number of myofibroblastic cancer-associated fibroblasts (CAF) was reduced after treatment. Based on single-cell sequencing analysis, OV-mOX40L, in combination with anti-IL6 and anti-PD-1, significantly extended the lifespan of PDAC mice. Conclusion:OV-mOX40L converted the immunosuppressive tumor immune microenvironment to a more activated state, remodeled the stromal matrix, and enhanced T cell response. OV-mOX40L significantly prolonged the survival of PDAC mice, either as a monotherapy or in combination with synergistic antibodies. Thus, this study provides a multimodal therapeutic strategy for pancreatic cancer treatment.
关键词	oncolytic virus pancreatic cancer OX40L tumor immune microenvironment T cell
URL	查看原文
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China["32271529","82273843"] ; China Postdoctoral Science Foundation[ZB19100123] ; Fundamental Research Funds for the Central Universities, Nankai University[XB202010] ; Key Research Fund of Tianjin Project and Team[20YFZCSY00450] ; Key Research and Development Program of Tianjin[82261138553] ; null[2020M670625]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:001042558200010
出版者	IVYSPRING INT PUBL
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/323572
专题	免疫化学研究所免疫化学研究所_公共科研平台_高通量筛选平台免疫化学研究所_公共科研平台_生物医学大数据平台免疫化学研究所_特聘教授组_张宏恺组
通讯作者	Zhang, Hongkai; Wang, Wei; Wang, Hui; Wang, Yuan
作者单位	1.Nankai Univ, State Key Lab Med Chem Biol, Tianjin, Peoples R China 2.Nankai Univ, Coll life Sci, Tianjin, Peoples R China 3.CNBG Nankai Univ Joint Res & Dev Ctr, Tianjin, Peoples R China 4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China 5.Tianjin First Cent Hosp, Dept Hematol, Tianjin 300192, Peoples R China
通讯作者单位	免疫化学研究所
推荐引用方式 GB/T 7714	Liu, Shiyu,Li, Fan,Ma, Qiongqiong,et al. OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment[J]. THERANOSTICS,2023,13(12).
APA	Liu, Shiyu.,Li, Fan.,Ma, Qiongqiong.,Du, Mingjuan.,Wang, Haoran.,...&Wang, Yuan.(2023).OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment.THERANOSTICS,13(12).
MLA	Liu, Shiyu,et al."OX40L-Armed Oncolytic Virus Boosts T-cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment".THERANOSTICS 13.12(2023).