Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model

Yuning Zhang; Chao Liu; Tao Wang; Fanxuan Kong; Huan Zhang; Jing Yi; Xiwen Dong; Han Duan; Ning Tao; Yuefeng Yang; Hua Wang

doi:10.1016/j.omto.2022.01.007

Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model

Mol Ther Oncolytics. 2022 Feb 1:24:486-496. doi: 10.1016/j.omto.2022.01.007. eCollection 2022 Mar 17.

Authors

Yuning Zhang¹, Chao Liu¹, Tao Wang², Fanxuan Kong^{1

3}, Huan Zhang⁴, Jing Yi¹, Xiwen Dong¹, Han Duan¹, Ning Tao¹, Yuefeng Yang⁵, Hua Wang¹

Affiliations

¹ Department of Experimental Haematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, P.R. China.
² Oncology Department, The Fifth Medical Center of PLA General Hospital, Beijing 100071, P.R. China.
³ PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, P.R. China.
⁴ Department of Critical Care Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China.
⁵ Department of Experimental Medical Science, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo 315000, Zhejiang Province, P.R. China.

Abstract

Oncolytic adenoviruses (OAds) are alternative immune therapeutic strategies for tumors. However, liver uptake and antibody neutralization are two major barriers for systemic delivery during the treatment of tumor metastasis. Mesenchymal stem cells (MSCs) have emerged as potential vehicles to improve delivery. In this study, we loaded umbilical-cord-derived MSCs (UC-MSCs) with OAds expressing decorin (rAd.DCN) or without foreign genes (rAd.Null) to treat breast cancer lung metastasis. In vivo, rAd.Null, MSCs.Null, and rAd.DCN exhibited antitumor effects compared with other groups in a mouse model. Unexpectedly, MSCs.Null showed much greater antitumor responses than MSCs.DCN, including improved survival and reduced tumor burden. Compared with rAd.Null, both MSCs.Null and MSCs.DCN could improve the viral spread and distribution in metastatic tumor lesions in the lung. MSCs.DCN produced much more decorin in lungs than rAd.DCN; however, rAd.DCN reduced the downstream target genes of decorin much more strongly than MSCs.DCN, which was consistent with in vitro findings. In addition, rAd.DCN, MSCs.Null, and MSCs.DCN could reduce The cytokine levels in the lung. In conclusion, MSCs improved oncolytic adenoviral delivery and spread in tumor tissues and enhanced therapeutic effects. However, MSCs.DCN reduced OAd-evoked antitumor responses, possibly via a contact-dependent mechanism.

Keywords: breast cancer lung metastatic; decorin; immune therapy; mesenchymal stem cell; oncolytic adenovirus.