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

Kyeong Tae Kim1, Jeong Hyun Lee1, Su Jin Kang1

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Engineered extracellular vesicles (M1EV_IL2) reprogram the tumor microenvironment by activating macrophages and T cells. This novel cancer immunotherapy enhances both innate and adaptive immune responses for improved therapeutic efficacy.

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T cell activationcancer immunotherapyextracellular vesiclesinterleukin-2macrophage repolarization

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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.