Mahsa Taghavi-Farahabadi, Mohammad Mahmoudi, Nazanin Mojtabavi, Farshid Noorbakhsh, Hossein Ghanbarian, Ameneh Koochaki, Seyed Mahmoud Hashemi, Nima Rezaei
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Enhancing the anti-tumor activity and reprogramming M2 macrophages by delivering siRNAs against SIRPα and STAT6 via M1 exosomes and combining with anti-PD-L1.
Background: The invasive property of breast cancer and the complex composition of the tumor microenvironment (TME) antibodies like anti-PD-L1, can inhibit tumor growth by promoting macrophage phagocytosis. In this research, we used anti-PD-L1 antibody and siRNAs targeting SIRPα (siSIRPα) and STAT6 (siSTAT6). The siRNAs were transported to macrophages using M1-derived exosomes.
Methods: For this purpose, exosomes were isolated from the supernatant of lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Next, siSIRPα and siSTAT6 were electroporated into the M1-exosomes. M1-exosomes without siRNA or loaded with different siRNAs were used to treat M2 macrophages. Then, the polarization of macrophages was evaluated. By co-culturing of treated macrophages with 4T1 cells, anti-tumor functions of macrophages were assessed.
Results: It was demonstrated that siRNA-loaded M1-exosomes induced macrophage polarization into an M1 phenotype and promoted the anti-tumor effects of macrophages as shown by a reduction in migration, invasion and proliferation of 4T1 cells, as well as an enhancement of phagocytosis of 4T1 cells by macrophages.
Conclusion: This study demonstrated the potential of a multifaceted therapeutic approach targeting TAMs to enhance anti-tumor immune responses in breast cancer.
期刊介绍：
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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