Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is aggressive, with variable responses to chemo-immune therapy.
• Understanding the TNBC tumor microenvironment is crucial for developing new immune-targeting agents.
• Galectin-3 (Gal-3) secreted by TNBC cells was previously shown to induce immunosuppression by inhibiting CD45 signaling in T cells.

Purpose of the Study:

• To investigate the interaction between secreted Gal-3 and T cells in TNBC.
• To elucidate the mechanism by which Gal-3 influences the tumor immune microenvironment.
• To identify potential therapeutic targets for TNBC.

Main Methods:

• CRISPR/Cas9 gene editing to create Gal-3 negative (Gal-3neg) TNBC cell lines.
• In vitro co-culture of Gal-3neg TNBC cells with peripheral blood mononuclear cells (PBMCs).
• In vivo studies using mice implanted with Gal-3 positive (Gal-3pos) and Gal-3neg TNBC tumors.
• RNA sequencing of T cells from TNBC patients and in vitro models.
• Analysis of T cell populations, including regulatory T cells (Tregs) and exhausted T cells.

Main Results:

• Gal-3neg tumors showed decelerated growth in mice after PBMC inoculation compared to Gal-3pos tumors.
• Gal-3pos tumors continued to grow with increased Treg infiltration despite PBMC inoculation.
• T cells from TNBC patients with high Gal-3 levels exhibited reduced oxidative phosphorylation gene expression.
• In vitro, Gal-3pos TNBCs led to mitochondrial dysfunction, increased reactive oxygen species in CD8 T cells, and a rise in exhausted T cells.

Conclusions:

• Secreted Gal-3 by TNBC cells promotes immunosuppression by upregulating CD4 T regulatory cells and CD8 T exhausted cells.
• Gal-3 negatively impacts T cell function, specifically oxidative phosphorylation and mitochondrial activity.
• Targeting the Gal-3-mediated immunosuppression pathway presents a potential therapeutic strategy for TNBC.