Engineered Endosymbionts that Modulate Primary Macrophage Function and Attenuate Tumor Growth by Shifting the Tumor Microenvironment

TL;DR

Scientists engineered bacteria that live inside immune cells to change their behavior and reduce tumor growth in mice.

Contribution

They developed engineered endosymbionts that secrete transcription factors to modulate macrophage function and tumor microenvironments.

Findings

Engineered strains altered macrophage gene expression and metabolic patterns in vitro.

In vivo, the strains shifted immune cell composition and reduced tumor growth in a breast cancer model.

Multiple doses of the strains were well-tolerated in mice.

Abstract

Modulating gene expression in macrophages can be used
to improve
tissue regeneration and redirect tumor microenvironments (TMEs) toward
positive therapeutic outcomes. We have developed as an engineered endosymbiont (EES) capable
of residing inside the eukaryotic host cell cytoplasm and controlling
the fate of macrophages. Secretion of mammalian transcription factors
(TFs) from that expresses
listeriolysin O (LLO; allowing the EES to escape destruction by the
macrophage) modulated expression of surface markers, cytokines, and
chemokines, indicating functional changes in a macrophage/monocyte
cell line. The engineered LLO TF strains were evaluated in murine bone marrow-derived macrophages
(BMDMs) by flow cytometry, chemokine/cytokine profiling, metabolic
assays, and RNA-Seq delivery of TFs by the EES shifted BMDM gene expression,
production of cytokine and chemokines, and metabolic patterns, indicating
that the TF strains could guide primary macrophage function. Thereafter,
the ability of the TF strains to alter the TME was characterized in
vivo in an orthotopic murine model of triple-negative breast cancer
to assess therapeutic effects. The TF strains altered the TME by shifting
immune cell composition and attenuating tumor growth. Additionally,
multiple doses of the TF strains were well-tolerated by the mice.
The use of LLO TF strains
as EES showed promise as a unique cancer immunotherapy by directing
the immune function intracellularly. The uses of EES could be expanded
to modulate other mammalian cells over a range of biomedical applications.

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