{"title":"Decorin-armed oncolytic adenovirus promotes natural killers (NKs) activation and infiltration to enhance NK therapy in CRC model.","authors":"Xue Li, Yuning Zhang, Zhuang Mao, Huiqiang Zhao, Hu Cao, Jingyi Wang, Wei Liu, Shiyun Dai, Yuefeng Yang, Yuanyuan Huang, Hua Wang","doi":"10.1186/s43556-024-00212-z","DOIUrl":null,"url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a prevalent malignant tumor of the gastrointestinal system, with the third and second highest incidence and mortality rates globally in 2020, respectively. Immunotherapy has developed rapidly in recent years. Natural killer (NK) cells have received increasing attention in the field of tumor immunotherapy due to their recognition and killing tumor cells without the limitations of major histocompatibility complexes. However, constraints within the tumor microenvironment that impede the infiltration and proliferation of NK cells result in poor efficacy of NK cell therapy for solid tumors. Oncolytic viral therapy is an immunogenic treatment with the potential to enhance anti-tumour immune responses and promote immune cell infiltration. In this study, we synergistically combine NK cells with an oncolytic adenovirus carrying Decorin (rAd.DCN) for the treatment of colorectal cancer (CRC) in a xenograft mouse model. By using Flow cytometry, real-time quantitative PCR and Calcein-AM release assay, we found that rAd.DCN could effectively promote proliferation, activation and degranulation of NK cells, up-regulate expression and secretion of NK cell killing activity-related factors, and enhance their killing activity. The efficacy is better than that of the blank control oncolytic virus rAd.Null. Combined treatment significantly inhibited tumor growth, increased the number of NK cells in peripheral blood, promoted the killing function of NK cells, and increased the expression levels of perforin and IFN-γ. At the same time, more NK cells were recruited to infiltrate tumor tissue. Our study established the feasibility of combination NK cells and oncolytic adenovirus application, thus expanding the scope of potentially curative treatments for NK cells in CRC.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527862/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular biomedicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s43556-024-00212-z","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Colorectal cancer (CRC) is a prevalent malignant tumor of the gastrointestinal system, with the third and second highest incidence and mortality rates globally in 2020, respectively. Immunotherapy has developed rapidly in recent years. Natural killer (NK) cells have received increasing attention in the field of tumor immunotherapy due to their recognition and killing tumor cells without the limitations of major histocompatibility complexes. However, constraints within the tumor microenvironment that impede the infiltration and proliferation of NK cells result in poor efficacy of NK cell therapy for solid tumors. Oncolytic viral therapy is an immunogenic treatment with the potential to enhance anti-tumour immune responses and promote immune cell infiltration. In this study, we synergistically combine NK cells with an oncolytic adenovirus carrying Decorin (rAd.DCN) for the treatment of colorectal cancer (CRC) in a xenograft mouse model. By using Flow cytometry, real-time quantitative PCR and Calcein-AM release assay, we found that rAd.DCN could effectively promote proliferation, activation and degranulation of NK cells, up-regulate expression and secretion of NK cell killing activity-related factors, and enhance their killing activity. The efficacy is better than that of the blank control oncolytic virus rAd.Null. Combined treatment significantly inhibited tumor growth, increased the number of NK cells in peripheral blood, promoted the killing function of NK cells, and increased the expression levels of perforin and IFN-γ. At the same time, more NK cells were recruited to infiltrate tumor tissue. Our study established the feasibility of combination NK cells and oncolytic adenovirus application, thus expanding the scope of potentially curative treatments for NK cells in CRC.
带装饰素的溶瘤腺病毒可促进自然杀伤因子(NKs)的激活和浸润,从而增强对 CRC 模型的 NK 治疗。
结直肠癌(CRC)是一种常见的消化系统恶性肿瘤,2020 年其发病率和死亡率分别居全球第三位和第二位。近年来,免疫疗法发展迅速。自然杀伤(NK)细胞不受主要组织相容性复合物的限制,可识别和杀伤肿瘤细胞,因此在肿瘤免疫治疗领域受到越来越多的关注。然而,肿瘤微环境的限制阻碍了 NK 细胞的浸润和增殖,导致 NK 细胞治疗实体瘤的疗效不佳。溶瘤病毒疗法是一种免疫原性疗法,具有增强抗肿瘤免疫反应和促进免疫细胞浸润的潜力。在本研究中,我们将 NK 细胞与携带 Decorin 的溶瘤腺病毒(rAd.DCN)协同结合,在异种移植小鼠模型中治疗结直肠癌(CRC)。通过流式细胞术、实时定量 PCR 和 Calcein-AM 释放试验,我们发现 rAd.DCN 能有效促进 NK 细胞的增殖、活化和脱颗粒,上调 NK 细胞杀伤活性相关因子的表达和分泌,增强其杀伤活性。其疗效优于空白对照溶瘤病毒rAd.Null。联合治疗能明显抑制肿瘤的生长,增加外周血中 NK 细胞的数量,促进 NK 细胞的杀伤功能,提高穿孔素和 IFN-γ 的表达水平。同时,更多的 NK 细胞被招募到肿瘤组织中。我们的研究确立了NK细胞和溶瘤腺病毒联合应用的可行性,从而扩大了NK细胞治疗CRC的潜在治疗范围。