Objective To investigate the effects of lentivirus-mediated overexpression of interferon gamma (IFN-γ) and soluble programmed death 1 (sPD-1) on the biological activity and genetic stability of bone marrow mesenchymal stem cells (BMSCs). Methods BMSCs were isolated and cultured by whole bone marrow adhesion method. The expression of surface markers of BMSCs was identified by flow cytometry. IFN-γ and sPD-1 gene sequences with green fluorescent protein (GFP) and red fluorescent protein (RFP) were amplified, and BMSCs overexpressing IFN-γ, sPD-1, and IFN-γ/sPD-1 were constructed by lentiviral transfection. The cell morphology was observed using an inverted microscope. The mRNA and protein expression of IFN-γ and sPD-1 were detected by real-time fluorescence quantitative PCR and Western blot analysis, respectively. The biological activity of the IFN-γ and sPD-1 overexpression BMSCs was assessed through functional assays, while their genetic stability was analysed using karyotyping. Results BMSCs positive for CD44 and CD105 and negative for CD34, CD11b and CD45 were successfully isolated and cultured. Compared with the empty group, IFN-γ and sPD-1 mRNA expression levels were significantly higher in the combined IFN-γ/sPD-1 group, but the growth of cells was similar in all groups; the telomerase activity was significantly reduced in the IFN-γ group, but the changes in telomerase activity were not obvious in the sPD-1 group and the combined IFN-γ/sPD-1 group. Conclusion BMSCs overexpressing IFN-γ and sPD-1 in combination has high biological activity and genetic stability.

01 Aug 2024·International Immunopharmacology

A PD-L1 tropism-expanded oncolytic adenovirus enhanced gene delivery efficiency and anti-tumor effects

Article

Author: Vong, Eu Gene ; Peng, Shanshan ; Mei, Shengsheng ; Zhan, Jinbiao

Recombinant adenovirus serotype 5 (Ad5)-mediated virotherapy is a maturing technique in cancer treatment. However, the utility of adenovirus (Ad) has been limited by low expression of coxsackievirus and adenovirus receptor (CAR) in cancer cells resulting in poor infectivity of Ads. To overcome the problem, we aimed to develop a novel tropism-modified oncolytic adenovirus, ZD55-F-HI-sPD-1-EGFP, which contains the epitope of PD-1 (70-77aa) at the HI-loop of Ad fiber. Trimerization of Fiber-sPD-1 was confirmed by immunoblot analysis. ZD55-F-HI-sPD-1-EGFP shows a remarkable improvement in viral infection rate and gene transduction efficiency in the PD-L1-positive cancer cells. Competition assays with a PD-L1 protein reveals that cell internalization of ZD55-F-HI-sPD-1-EGFP is mediated by both CAR and PD-L1 at a high dose. The progeny virus production capacity showed that sPD-1 incorporated fiber-modified oncolytic Ad replication was not affected. Furthermore, treating with ZD55-F-HI-sPD-1-EGFP significantly increased viral infection rate and enhanced anti-tumor effect in vivo. This study demonstrates that the strategy to expand tropism of oncolytic Ad may significantly improve therapeutic profile for cancer treatment.

06 Apr 2023·International journal of molecular sciences

Engineering a HER2-CAR-NK Cell Secreting Soluble Programmed Cell Death Protein with Superior Antitumor Efficacy.

Article

Author: Qi, Xin ; Li, Hongyan ; Zhang, Xiaomin ; Li, Jing ; Li, Mingfeng ; Chen, Junsheng ; Xiong, Ying ; Chen, Jiaxin ; Xia, Wenjiao ; Xu, Hui ; Hou, Wenqing ; Xie, Zuoquan

A new therapy strategy for relapsing patients who have received trastuzumab treatment urgently needs to be explored. HER2-specific chimeric antigen receptor (CAR)-expressing NK cells are being rapidly developed for solid tumor therapy, as they have many advantages over HER2-CAR-T cells. Endogenous soluble PD-1 (sPD-1) from the PD-1 extracellular domain blocks PD-1/PD-L1 interaction to promote cancer immunology. Herein, we engineered a new HER2-CAR-NK cell that co-expresses sPD-1 (designed as sPD-1-CAR-NK cells) and assessed its cytotoxic activities toward various cancer cells, activation of immunity and sPD-1 release in vitro and in mouse models bearing breast cancer cells with high HER2 expression, with or without trastuzumab resistance. We demonstrated that sPD-1-CAR-NK cells were able to release bioactive sPD-1, thereby enhancing the cytolytic activities of HER2-CAR-NK cells against HER2 and PD-L1 highly expressing target cells accompanied by increases in the secretion of perforin, granzyme B and IFN-γ. In vivo, sPD-1-CAR-NK cells had superior immunological anticancer efficacy compared to HER2-CAR-NK cells, and they had advantages over HER2-CAR-NK cells in the intraperitoneal injection of sPD-1. Moreover, the infiltration and activation of NK and T cells into tumor tissue were increased in mice with sPD-1-CAR-NK cells. There was no significant change in the body temperature, organ tissue and body weight in all groups except for the group with the PD-1 injection. Together, these data indicate that HER2-specific sPD-1-CAR-NK cells can transport sPD-1 into cancer tissues with high HER2 expression, further improving the efficacy of HER-CAR-NK cells without obvious side effects. sPD-1-CAR-NK is a promising cytotherapeutic agent for patients bearing HER2-positive breast cancer, including those with trastuzumab resistance.

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