Interleukin-2 Surface Displayed M1 Macrophage-Derived Extracellular Vesicles for Modulating the Tumor...

Area of Science:

• Immunology
• Biotechnology
• Cancer Research

Background:

• Cancer immunotherapy faces challenges due to the immunosuppressive tumor microenvironment (TME), characterized by M2 macrophages and non-effector T cells.
• Modulating the TME is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To develop a multifunctional cancer immunotherapeutic agent, M1EV_IL2, by surface-modifying M1 macrophage-derived extracellular vesicles (M1EV) to display interleukin-2 (IL-2).
• To engineer M1EV_IL2 to simultaneously modulate innate (macrophages) and adaptive (T cells) immune responses within the TME.

Main Methods:

• Engineered M1EV using metabolic glycoengineering to introduce azide groups, followed by bioorthogonal chemistry to display IL-2, creating M1EV_IL2.
• Purified and characterized M1EV_IL2 using size-exclusion chromatography (SEC) and nanoparticle tracking analysis (NTA).
• Evaluated M1EV_IL2 in vitro for macrophage repolarization and T cell activation, and ex vivo for T cell proliferation, cytokine secretion, and activation marker expression.

Main Results:

• M1EV_IL2 demonstrated stable IL-2 display and retained EV properties, inducing M2-to-M1 macrophage repolarization by upregulating M1 markers (IL-1β, CXCL10) and downregulating M2 markers (CD206).
• M1EV_IL2 activated CD4+ T cells and converted naïve CD8+ T cells into effector T cells.
• Enhanced T cell proliferation and secretion of antitumor cytokines were observed.

Conclusions:

• M1EV_IL2 effectively reshapes the tumor immune landscape by co-activating macrophages and T cells, boosting both innate and adaptive immunity.
• This approach offers a potential alternative to direct tumor-targeting therapies, aiming to mitigate adverse effects and improve overall therapeutic outcomes in cancer treatment.