An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation
Introduction: Hypoxia 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. Methods: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823004097 |
| _version_ | 1797365582427848704 |
|---|---|
| author | Yu Chen Jialun Wang Ying Huang Jianzhuang Wu Yue Wang Aotian Chen Qiyuan Guo Yixuan Zhang Shu Zhang Lei Wang Xiaoping Zou Xihan Li |
| author_facet | Yu Chen Jialun Wang Ying Huang Jianzhuang Wu Yue Wang Aotian Chen Qiyuan Guo Yixuan Zhang Shu Zhang Lei Wang Xiaoping Zou Xihan Li |
| author_sort | Yu Chen |
| collection | DOAJ |
| description | Introduction: Hypoxia 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. Methods: A 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. Results: The 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. Conclusion: The 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. |
| first_indexed | 2024-03-08T16:52:00Z |
| format | Article |
| id | doaj.art-6ef9545434e94fbbbe91f031dd12de1f |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-08T16:52:00Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-6ef9545434e94fbbbe91f031dd12de1f2024-01-05T04:23:23ZengElsevierPharmacological Research1096-11862024-01-01199107053An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activationYu Chen0Jialun Wang1Ying Huang2Jianzhuang Wu3Yue Wang4Aotian Chen5Qiyuan Guo6Yixuan Zhang7Shu Zhang8Lei Wang9Xiaoping Zou10Xihan Li11Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaDepartment of Pain, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Corresponding authors.Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Corresponding authors.Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; Corresponding author at: Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.Introduction: Hypoxia 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. Methods: A 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. Results: The 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. Conclusion: The 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.http://www.sciencedirect.com/science/article/pii/S1043661823004097Oncolytic systemHypoxiaPhotodynamic therapyImmune activationPancreatic tumor |
| spellingShingle | Yu Chen Jialun Wang Ying Huang Jianzhuang Wu Yue Wang Aotian Chen Qiyuan Guo Yixuan Zhang Shu Zhang Lei Wang Xiaoping Zou Xihan Li An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation Pharmacological Research Oncolytic system Hypoxia Photodynamic therapy Immune activation Pancreatic tumor |
| title | An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| title_full | An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| title_fullStr | An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| title_full_unstemmed | An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| title_short | An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| title_sort | oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation |
| topic | Oncolytic system Hypoxia Photodynamic therapy Immune activation Pancreatic tumor |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823004097 |
| work_keys_str_mv | AT yuchen anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT jialunwang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yinghuang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT jianzhuangwu anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yuewang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT aotianchen anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT qiyuanguo anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yixuanzhang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT shuzhang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT leiwang anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT xiaopingzou anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT xihanli anoncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yuchen oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT jialunwang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yinghuang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT jianzhuangwu oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yuewang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT aotianchen oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT qiyuanguo oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT yixuanzhang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT shuzhang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT leiwang oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT xiaopingzou oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation AT xihanli oncolyticsystemproducesoxygenselectivelyinpancreatictumorcellstoalleviatehypoxiaandimproveimmuneactivation |