Radiotherapy-derived engineered stem cell exosomes improve anti-glioma immunotherapy by promoting the formation of tertiary lymphoid structure and improve the release of type I interferon.

in Journal of nanobiotechnology by Man Li, Lisen Lu, Qiuhong Bao, Minghui Zhou, Bin Nie, Yanchao Liu, Kai Shu, Ting Lei, Mingxin Zhu

TLDR

  • This study investigates novel therapeutic approaches to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures within the glioma microenvironment to enhance natural and adaptive immune responses.

Abstract

The absence of signaling pathways related to intrinsic immune activation in tumor cells and the immunosuppressive microenvironment limit lymphocyte infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study investigates strategies to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures (TLS) within the glioma microenvironment (GME) to enhance natural and adaptive immune responses. We successfully induced antigen-presenting cell activation, macrophage/microglia polarization, and TLS formation in GME by intracranial delivery of BafA1@Rexo-SC, which comprises exosomes from irradiated bone marrow-derived stem cells overexpressing CD47 nanobodies and STING, loaded with the autophagy inhibitor BafA1. These exosomes efficiently activated the cGAS-STING pathway, leading to the formation of "lymphoid tissue organizer cells (Lto)" cells, VEGFA release for high endothelial microvessel formation, and chemokine release for T and B cell recruitment. BafA1@Rexo-SC also promoted macrophage phagocytosis of tumor cells and enhanced effector T cell function by blocking CD47, while releasing type I interferon. Our findings suggest novel therapeutic approaches for glioma treatment.

Overview

  • The study aims to investigate strategies to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures within the glioma microenvironment to enhance natural and adaptive immune responses.
  • The researchers developed BafA1@Rexo-SC, a novel therapeutic approach consisting of exosomes loaded with BafA1, a potent autophagy inhibitor, and CD47 nanobodies and STING, a key molecule in the cGAS-STING pathway.
  • The primary objective of the study is to develop a novel therapeutic approach that can effectively activate the intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures, ultimately enhancing natural and adaptive immune responses.

Comparative Analysis & Findings

  • The study found that BafA1@Rexo-SC induces antigen-presenting cell activation, macrophage/microglia polarization, and tertiary lymphoid structure formation within the glioma microenvironment.
  • The therapy promotes the formation of lymphoid tissue organizer cells (Lto) cells, releases VEGFA for high endothelial microvessel formation, and chemokine release for T and B cell recruitment.
  • BafA1@Rexo-SC also enhances macrophage phagocytosis of tumor cells, blocks CD47, and releases type I interferon, ultimately promoting effector T cell function.

Implications and Future Directions

  • The study's findings suggest that BafA1@Rexo-SC may be a novel therapeutic approach for glioma treatment.
  • Further research is necessary to fully understand the effects of BafA1@Rexo-SC on glioma cells and the tumor microenvironment.
  • Future studies could explore the combination of BafA1@Rexo-SC with other immunotherapies to enhance its therapeutic potential.
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