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.

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2024-12-13 DOI:10.1016/j.lfs.2024.123311

Mahsa Taghavi-Farahabadi, Mohammad Mahmoudi, Nazanin Mojtabavi, Farshid Noorbakhsh, Hossein Ghanbarian, Ameneh Koochaki, Seyed Mahmoud Hashemi, Nima Rezaei

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Abstract

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.

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背景：乳腺癌具有侵袭性，肿瘤微环境（TME）成分复杂，而抗 PD-L1 等抗体可通过促进巨噬细胞吞噬作用抑制肿瘤生长。在这项研究中，我们使用了抗 PD-L1 抗体和靶向 SIRPα （siSIRPα）和 STAT6 （siSTAT6）的 siRNAs。siRNA 通过 M1 衍生的外泌体被转运至巨噬细胞：为此，从脂多糖（LPS）刺激的 RAW264.7 细胞的上清液中分离出外泌体。然后，将 siSIRPα 和 siSTAT6 电穿孔到 M1-外泌体中。用不含 siRNA 或含有不同 siRNA 的 M1 外泌体处理 M2 巨噬细胞。然后，对巨噬细胞的极化进行评估。通过将处理过的巨噬细胞与 4T1 细胞共培养，评估了巨噬细胞的抗肿瘤功能：结果：研究表明，siRNA负载的M1-外泌体可诱导巨噬细胞极化为M1表型，并促进巨噬细胞的抗肿瘤作用，具体表现为减少4T1细胞的迁移、侵袭和增殖，以及增强巨噬细胞对4T1细胞的吞噬作用：这项研究表明，针对TAMs的多方面治疗方法具有增强乳腺癌抗肿瘤免疫反应的潜力。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

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.