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Published on: November 28, 2019
MicroRNA-induced reprogramming of tumor-associated macrophages for modulation of tumor immune microenvironment
Yina Wu1, Jinwon Park1, Enzhen Xu1
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
Abstract:
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and typically exhibit pro-tumoral phenotypes. TAMs overexpress the signal regulatory protein alpha (SIRPα) receptor on their surface, which interacts with CD47 on tumor cells to inhibit their phagocytic activity. In this study, we developed lipid nanoparticles modified with an anti-SIRPα antibody (aSIRPα) for the targeted delivery of microRNA-155 (miR155@aSIRPα-LNP) to TAMs, aiming to enhance their anti-tumoral phenotypes within the tumor microenvironment. The aSIRPα modification not only facilitated nanoparticle uptake by TAMs rather than B16F10 cells, but also blocked the anti-phagocytosis signal by disrupting the interaction between SIRPα and CD47 on cancer cells. This dual functionality enhanced the expression of anti-tumoral phenotype markers in TAMs and activated macrophage-mediated phagocytosis of tumor cells. In a melanoma model, intratumoral administration of miR155@aSIRPα-LNP to B16F10 tumor-bearing mice reprogrammed TAMs toward anti-tumoral phenotypes. The anti-tumoral cytokines released by these TAMs remodeled the immunosuppressive tumor microenvironment, increasing cytotoxic T cell infiltration and reducing the regulatory T cell population, inhibiting tumor progression. This approach indicates the potential of miRNA-based therapies to overcome the limitations of current immunotherapies in treating cold solid tumors. Overall, the results suggest that delivering miR155 to TAMs by targeting SIRPα is a promising strategy for modulating the immunosuppressive tumor microenvironment in cancer immunotherapy.
Insights
Targeting tumor-associated macrophages (TAMs) with anti-SIRPα antibody-modified nanoparticles delivering microRNA-155 (miR155@aSIRPα-LNP) reprogrammed TAMs to an anti-tumoral phenotype, enhancing cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Nanomedicine
Background:
- Tumor-associated macrophages (TAMs) are prevalent in the tumor microenvironment and often promote tumor growth.
- TAMs express signal regulatory protein alpha (SIRPα), which binds CD47 on tumor cells, inhibiting phagocytosis.
- Current immunotherapies face challenges in treating cold solid tumors due to the immunosuppressive tumor microenvironment.
Purpose of the Study:
- To develop a targeted nanoparticle delivery system for microRNA-155 (miR155) to TAMs.
- To reprogram TAMs towards an anti-tumoral phenotype and enhance anti-cancer immunity.
- To investigate the potential of this approach in overcoming limitations of current immunotherapies for solid tumors.
Main Methods:
- Lipid nanoparticles were engineered with an anti-SIRPα antibody (aSIRPα) for targeted delivery of miR155 (miR155@aSIRPα-LNP).
- Nanoparticle uptake and interaction with TAMs and B16F10 melanoma cells were assessed.
- The effect of miR155@aSIRPα-LNP on TAM phenotype, phagocytosis, and the tumor microenvironment was evaluated in a melanoma mouse model.
Main Results:
- The aSIRPα modification ensured targeted uptake of nanoparticles by TAMs, not tumor cells.
- The nanoparticles disrupted the SIRPα-CD47 interaction, blocking the anti-phagocytosis signal.
- miR155@aSIRPα-LNP treatment reprogrammed TAMs to an anti-tumoral phenotype, increasing phagocytosis and releasing anti-tumoral cytokines.
- This remodeling of the tumor microenvironment led to increased cytotoxic T cell infiltration and reduced regulatory T cells, inhibiting tumor progression.
Conclusions:
- Targeting SIRPα on TAMs with miR155-loaded nanoparticles is a viable strategy to modulate the immunosuppressive tumor microenvironment.
- This approach enhances macrophage-mediated anti-tumor activity and promotes T cell-mediated immunity.
- miR155@aSIRPα-LNP represents a promising therapeutic strategy for enhancing cancer immunotherapy, particularly for cold solid tumors.
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