Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• In vitro studies suggest proteasome inhibitors may treat triple-negative breast cancer (TNBC).
• The role of specific proteasome subunits in TNBC response and prognosis is not fully understood.

Purpose of the Study:

• To investigate the efficacy of proteasome inhibitors in TNBC.
• To explore the correlation between proteasome subunit expression and treatment sensitivity.
• To determine the impact of proteasome activity on anti-tumor immunity and metastasis.

Main Methods:

• In vitro treatment of TNBC cell lines with bortezomib and carfilzomib.
• Analysis of proteasome subunit expression (immuno- vs. constitutive).
• Transcriptome analysis and genomic copy number profiling.
• Assessment of tumor-infiltrating lymphocytes (TILs), MHC-I, and PA28β expression.
• Comparison of β5i expression in primary tumors versus brain metastases.

Main Results:

• Bortezomib and carfilzomib induced proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cells.
• Sensitivity correlated with immuno-proteasome (PSMB8/9/10) but not constitutive proteasome subunit expression.
• High immuno-proteasome expression was linked to favorable prognosis in adjuvant treatment settings.
• Tumor β5i expression correlated with MHC-I, PA28β, and TILs.
• TILs conferred protection in high β5i TNBCs, but not in low β5i tumors.
• β5i expression was significantly lower in brain metastases compared to primary tumors.

Conclusions:

• Targeting immuno-proteasomes may potentiate anti-TNBC immunity, suggesting proteasome inhibitors could be counterproductive in adjuvant settings.
• Suppression of β5i may facilitate immune evasion and metastatic progression in TNBC.
• Understanding proteasome subunit dynamics is crucial for optimizing TNBC treatment strategies.