TNBC-derived Gal3BP/Gal3 complex induces immunosuppression through CD45 receptor

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Triple negative breast cancer (TNBC) is aggressive and often resistant to immunotherapy.
• Extracellular vesicles (EVs) secreted by TNBC cells can reprogram the tumor microenvironment and hinder immune responses.
• Galectin 3 (Gal3), found in breast cancer cells, downregulates T-cell receptor expression by binding to receptors like CD45.

Purpose of the Study:

• To investigate the association between Gal3, TNBC-secreted EVs, and immunosuppression via the CD45 signaling pathway.
• To elucidate a novel tumor escape mechanism in TNBC.

Main Methods:

• Isolation of EVs from TNBC cell lines (MDA-MB-231) and patient plasma.
• Mass spectrometry to identify proteins within EVs.
• Co-culture of peripheral blood mononuclear cells (PBMCs) with tumor-derived EVs and Gal3BP/Gal3 complex.
• Blocking the CD45 receptor in co-cultured PBMCs.

Main Results:

• TNBC-secreted EVs contain Gal3 binding protein (Gal3BP) that interacts with Gal3.
• The Gal3BP/Gal3 complex significantly increases T-regulatory cells and suppressive interleukins (IL-10, IL-35) in PBMCs.
• Blocking CD45 on PBMCs reversed EV-mediated immunosuppression, increasing IFN-γ and activating CD4, CD8, and CD56 effector cells.

Conclusions:

• TNBC utilizes a Gal3BP/Gal3 complex within EVs to induce immunosuppression through the CD45 pathway.
• This mechanism represents a novel tumor escape strategy for TNBC.
• Targeting this pathway could lead to new immunotherapy strategies for TNBC.