USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

• Published in: Molecular therapy. Oncolytics Vol. 23; pp. 26 - 37
• Main Authors: Xue, Vivian Weiwen, Chung, Jeff Yat-Fai, Tang, Philip Chiu-Tsun, Chan, Alex Siu-Wing, To, Travis Hoi-Wai, Chung, Justin Shing-Yin, Mussal, Francis, Lam, Eric W.-F., Li, Chunjie, To, Ka-Fai, Leung, Kam-Tong, Lan, Hui-Yao, Tang, Patrick Ming-Kuen
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 17.12.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: gene therapy; M1/M2 polarization; Mincle; Original; tumor-associated macrophages; ultrasound microbubble; USMB-shMincle; USMB-shMincle; gene therapy; Mincle; ultrasound microbubble; M1/M2 polarization; tumor-associated macrophages
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2021.08.010

Mincle is essential for tumor-associated macrophage (TAM)-driven cancer progression and represents a potential immunotherapeutic target for cancer. Nevertheless, the lack of a specific inhibitor has largely limited its clinical translation. Here, we successfully developed a gene therapeutic strategy for silencing Mincle in a virus-free and tumor-specific manner by combining RNA interference technology with an ultrasound-microbubble-mediated gene transfer system (USMB). We identified a small hairpin RNA (shRNA) sequence shMincle that can silence not only Mincle expression but also the protumoral effector production in mouse bone marrow- and human THP-1-derived macrophages in the cancer setting in vitro. By using our well-established USMB system (USMB-shMincle), the shMincle-expressing plasmids were delivered in a tissue-specific manner into xenografts of human lung carcinoma A549 and melanoma A375 in vivo. Encouragingly, we found that USMB-shMincle effectively inhibited the protumoral phenotypes of TAMs as well as the progression of both A549 and A375 xenografts in a dose-dependent manner in mice without significant side effects. Mechanistically, we identified that USMB-shMincle markedly enhanced the anticancer M1 phenotype of TAMs in the A549 and A375 xenografts by blocking the protumoral Mincle/Syk/nuclear factor κB (NF-κB) signaling axis. Thus, USMB-shMincle may represent a clinically translatable novel and safe gene therapeutic approach for cancer treatment. [Display omitted] Here, we successfully optimized our virus-free anticancer gene therapy USMB-shMincle against human lung carcinoma and melanoma. USMB-shMincle effectively suppresses progression of the tumor xenografts in a dose-dependent manner without detectable side-effects by blocking M1/M2 polarization in vivo, evidencing its translational potential as a novel immunotherapeutic startegy for cancer patients.