Sonodynamical reversion of immunosuppressive microenvironment in prostate cancer via engineered exosomes

Dingyi Wang; Zhuo Wan; Qian Yang; Jianmei Chen; Yunnan Liu; Fan Lu; Jie Tang

doi:10.1080/10717544.2022.2044937

Sonodynamical reversion of immunosuppressive microenvironment in prostate cancer via engineered exosomes

Drug Deliv. 2022 Dec;29(1):702-713. doi: 10.1080/10717544.2022.2044937.

Authors

Dingyi Wang¹, Zhuo Wan², Qian Yang¹, Jianmei Chen³, Yunnan Liu⁴, Fan Lu⁵, Jie Tang¹

Affiliations

¹ Department of Ultrasound, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
² Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi' an, People's Republic of China.
³ Department of Health Medicine, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China.
⁴ Department of Ultrasound, Tangdu Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
⁵ Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, People's Republic of China.

Abstract

Prostate cancer (PCa) responds poorly to routine immunotherapy due to the tumor immunosuppressive microenvironment. Here, we describe an ultrasound-based drug delivery strategy to stimulate potent anti-tumor immunity via exosomes encapsulated with sonosensitizers Chlorin e6 (Ce6) and immune adjuvant R848, namely Exo^Ce6+R848. Exo^Ce6+R848 was constructed by simple co-incubation of Ce6 and R848 with HEK 293T cell-derived exosomes. The properties of exosomes were not affected after loading Ce6 and R848, and the exosomes were accumulated in the tumor site after intratumoral injection. In vitro and in vivo assays showed that ultrasonic irradiation enhanced R848-mediated DCs maturation when Exo^Ce6+R848 was engulfed by DCs, as demonstrated by the upregulated expression of CD80 and CD86. Furthermore, these engineered exosomes together with ultrasound irradiation could synergistically reprogram macrophages from an immunosuppressive M2-like phenotype to an anti-tumor M1-like phenotype, further activating effector T cells and reverting the immunosuppressive microenvironment. The exosome delivery strategy not only supplies a paradigm for overcoming side effects of systemic delivery of Ce6 and R848, but also offers an effective combination regimen of cancer immunotherapy.

Keywords: Prostate cancer; exosomes; immunoadjuvant; sonodynamic therapy; synergistic effect.

MeSH terms

Cell Line, Tumor
Exosomes*
Humans
Immunotherapy
Male
Prostatic Neoplasms* / drug therapy
Tumor Microenvironment

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81471682, No. 81801708), China Postdoctoral Science Foundation (2021T140795), Shaanxi Province Natural Science Foundation (2020SF-079), and Xi 'an Science and Technology Plan Project (21YXYJ0134).