An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation

Yu Chen; Jialun Wang; Ying Huang; Jianzhuang Wu; Yue Wang; Aotian Chen; Qiyuan Guo; Yixuan Zhang; Shu Zhang; Lei Wang; Xiaoping Zou; Xihan Li

doi:10.1016/j.phrs.2023.107053

An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation

Pharmacol Res. 2024 Jan:199:107053. doi: 10.1016/j.phrs.2023.107053. Epub 2024 Jan 2.

Authors

Yu Chen¹, Jialun Wang¹, Ying Huang², Jianzhuang Wu³, Yue Wang⁴, Aotian Chen¹, Qiyuan Guo⁵, Yixuan Zhang¹, Shu Zhang¹, Lei Wang⁶, Xiaoping Zou⁷, Xihan Li⁸

Affiliations

¹ Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
² Department of Pain, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
³ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
⁴ Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.
⁵ Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing 210008, China.
⁶ Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: leiwang9631@nju.edu.cn.
⁷ Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: zouxp@nju.edu.cn.
⁸ 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. Electronic address: xihanli@nju.edu.cn.

PMID: 38176529
DOI: 10.1016/j.phrs.2023.107053

Abstract

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.

Keywords: Hypoxia; Immune activation; Oncolytic system; Pancreatic tumor; Photodynamic therapy.

MeSH terms

Cell Line, Tumor
Humans
Hypoxia / therapy
MicroRNAs*
Oxygen
Pancreatic Neoplasms* / genetics
Photochemotherapy*
Tumor Microenvironment

Substances

Oxygen
MicroRNAs