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

ABSTRACT: 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.

SUBMITTER: Xue VW

PROVIDER: S-EPMC8463747 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Xue Vivian Weiwen VW Chung Jeff Yat-Fai JY Tang Philip Chiu-Tsun PC Chan Alex Siu-Wing AS To Travis Hoi-Wai TH Chung Justin Shing-Yin JS Mussal Francis F Lam Eric W-F EW Li Chunjie C To Ka-Fai KF Leung Kam-Tong KT Lan Hui-Yao HY Tang Patrick Ming-Kuen PM

Molecular therapy oncolytics 20210825

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 hair ...[more]

PMID: 34589582

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Dataset Information

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

Publications

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

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