LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are aggressive subtypes with poor outcomes, necessitating novel therapeutic targets.
• LMP7 (β5i/PSMB8), an immunoproteasome subunit, is linked to inflammation-related cancers, but its role in TNBC and IBC is unclear.

Purpose of the Study:

• To investigate the function of LMP7 in TNBC and IBC pathogenesis.
• To evaluate the therapeutic potential of the selective LMP7 inhibitor M3258 in TNBC and IBC.

Main Methods:

• Analysis of LMP7 expression in human TNBC samples and its correlation with immune cell infiltration.
• In vitro studies using TNBC/IBC cell lines treated with M3258 to assess cell viability and apoptosis.
• In vivo studies in an immunocompetent TNBC/IBC model using M3258 to evaluate tumor growth, immune cell activity, and macrophage infiltration.
• Co-culture experiments to assess the interaction between TNBC/IBC cells and M2 macrophages.

Main Results:

• LMP7 expression in TNBC correlated with CD8+ T cell infiltration and activation.
• M3258 inhibited LMP7, reduced TNBC/IBC cell viability, and induced apoptosis in vitro.
• In vivo, M3258 decreased tumor growth, reduced M2 macrophages, and activated CD8+ T cells.
• M3258 suppressed M2 macrophage-enhanced TNBC/IBC cell invasiveness and inflammatory gene signatures.

Conclusions:

• LMP7 plays a role in shaping the pro-tumorigenic microenvironment in TNBC and IBC, partly via M2 macrophages.
• LMP7 inhibition with M3258 demonstrates therapeutic potential by reducing tumor progression and modulating the immune microenvironment.
• LMP7 represents a promising novel therapeutic target for aggressive breast cancer subtypes like TNBC and IBC.