Bioengineer mesenchymal stem cell for treatment of glioma by IL-12 mediated microenvironment reprogramming and nCD47-SLAMF7 mediated phagocytosis regulation of macrophages

High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors leading to the resistance of glioma to immunotherapy. This study constructed engineering MSCs expressing IL-12 and nCD47-SLAMF7 (anti-CD47 nanobody combined with the extracellular domain of SLAMF7). Intracranial injection of these two kinds of engineered MSCs could promote M1 polarization of infiltrating macrophages, phagocytosis of tumor cells by macrophages and antigen-presenting cells, and activation of effector T cells. In addition, the two kinds of engineered MSCs could also promote the release of a large number of pro-inflammatory cytokines in the tumor microenvironment, reverse the tumor-inhibitory immune microenvironment, and thus inhibit the development of glioma cells.

Abstract:

High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma’s resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self-molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow-derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor-homing characteristics upon activation by TGF-β. These MSCs are designed to secrete the anti-tumor immune cytokine IL-12 and the nCD47-SLAMF7 fusion protein, which regulates T-cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood-brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage-mediated tumor cell phagocytosis, activate antigen-presenting cells, and promote effector CD8+ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF-β at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients.

Author list:

Man Li†*, Lisen Lu†, Qungen Xiao, Ali Abdi Maalim, Bin Nie, Yanchao Liu, Ulf D. Kahlert, Kai Shu, Ting Lei, Mingxin Zhu

How to cite:

M. Li, L. Lu, Q. Xiao, A. A. Maalim, B. Nie, Y. Liu, U. D. Kahlert, K. Shu, T. Lei, M. Zhu, Exploration 2024, 20240027.
https://doi.org/10.1002/EXP.20240027