Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor

Zhan Hua; Shan Wu; Yulian Zhang; Xiuhong Wang; Ju Cui; Yunxuan Li; Chengcheng Yang; Min Zhai; Bo Deng; Bin Yu; Jian-Dong Huang; Zai Wang; Jianjun Zhou

doi:10.3389/fmed.2023.1284120

Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor

Front Med (Lausanne). 2023 Oct 31:10:1284120. doi: 10.3389/fmed.2023.1284120. eCollection 2023.

Authors

Zhan Hua^#¹, Shan Wu^#², Yulian Zhang^#³, Xiuhong Wang⁴, Ju Cui⁵, Yunxuan Li⁶, Chengcheng Yang⁷, Min Zhai⁸, Bo Deng⁸, Bin Yu^{9

10}, Jian-Dong Huang⁹, Zai Wang⁸, Jianjun Zhou²

Affiliations

¹ Department of General Surgery, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
² Research Center for Translational Medicine, Cancer Stem Cell Institute, East Hospital, Tongji University School of Medicine, Shanghai, China.
³ Department of Neurosurgery, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
⁴ Department of Pathology, China-Japan Friendship Hospital, Beijing, China.
⁵ The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
⁶ NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁷ Ningbo First Hospital, Ningbo, China.
⁸ Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
⁹ School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
¹⁰ HKND YB1 Pharmaceutical Limited, Hong Kong, Hong Kong SAR, China.

^# Contributed equally.

Abstract

Background: Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far.

Methods: The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors.

Results: We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis.

Conclusion: We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.

Keywords: Salmonella typhimurium; YB1; liver metastasis; pancreatic neuroendocrine tumor; targeted IFNγ therapy.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National High Level Hospital Clinical Research Funding (023-NHLHCRF-DJMS-01), transverse project (2018-HX-25), the Chinese Ministry of Science and Technology (MOST) Grant (2016YFA0101201) and the National Nature Science Foundation of China (No. 82073264).