An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation
An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation
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DOI：
10.1016/j.phrs.2023.107053
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发表时间：
2024-01-04
影响因子：
9.3
通讯作者：
Li，Xihan
中科院分区：
文献类型：
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作者：
Chen，Yu;Wang，Jialun;Li，Xihan
缺氧是目前胰腺癌治疗效果不佳的重要原因之一，胰腺癌致密的间质限制了氧在肿瘤内的扩散。我们利用各种实验在多个水平（细胞，类器官，在体内），以探讨其对胰腺癌的影响，并分析了免疫微环境的变化在其中的作用，通过高通量sequencing. ResultsAdv-MCK系统是一个溶瘤腺病毒系统表达三个特殊的基因组成部分。microRNA（miRNA）靶点（miRTs）使adv-MCK能够在胰腺癌细胞中选择性复制。过氧化氢酶催化胰腺癌细胞中过表达的过氧化氢以产生内源性氧，内源性氧被BiolerRed催化以产生单线态氧（1 O2）并进一步增强溶瘤作用。同时，adv-MCK系统可特异性改善胰腺癌组织的缺氧状态，与光动力疗法联合发挥抗肿瘤作用，并激活抗肿瘤免疫，尤其是通过提高肿瘤微环境中γδ T细胞的水平。结论响应性氧自供adv-MCK级联反应系统联合光动力疗法可改善胰腺癌组织缺氧微环境，增强抗肿瘤免疫，其为胰腺癌提供了有希望的替代治疗策略。
IntroductionHypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor.MethodsA responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing.ResultsThe adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment.ConclusionThe responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.