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ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer
Ukjin Kim1, Rahul Debnath2, Javier E Maiz1
1Department of Surgery, Sylvester Comprehensive Cancer, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Abstract:
Triple-negative breast cancer (TNBC) contributes greatly to mortality of breast cancer, demanding new targetable options. We have shown that TNBC patients have high ΔNp63 expression in tumors. However, the function of ΔNp63 in established TNBC is yet to be explored. In current studies, targeting ΔNp63 with inducible CRISPR knockout and Histone deacetylase inhibitor Quisinostat showed that ΔNp63 is important for tumor progression and metastasis in established tumors by promoting myeloid-derived suppressor cell (MDSC) survival through tumor necrosis factor alpha. Decreasing ΔNp63 levels are associated with decreased CD4+ and FOXP3+ T-cells but increased CD8+ T-cells. RNA sequencing analysis indicates that loss of ΔNp63 alters multiple MDSC properties such as lipid metabolism, chemotaxis, migration, and neutrophil degranulation besides survival. We further demonstrated that targeting ΔNp63 sensitizes chemotherapy. Overall, we showed that ΔNp63 reprograms the MDSC-mediated immunosuppressive functions in TNBC, highlighting the benefit of targeting ΔNp63 in chemotherapy-resistant TNBC.
Insights
Targeting delta Np63 (ΔNp63) in triple-negative breast cancer (TNBC) inhibits tumor progression and metastasis. This approach reprograms immunosuppressive myeloid-derived suppressor cells, enhancing chemotherapy sensitivity in resistant tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) has high mortality and lacks targeted therapies.
- High delta Np63 (ΔNp63) expression is observed in TNBC tumors.
- The role of ΔNp63 in established TNBC progression and metastasis remains unclear.
Purpose of the Study:
- To investigate the function of ΔNp63 in established TNBC.
- To explore targeting ΔNp63 as a therapeutic strategy for TNBC.
- To understand how ΔNp63 influences the tumor microenvironment and immune response.
Main Methods:
- Utilized inducible CRISPR knockout to target ΔNp63.
- Administered Histone deacetylase inhibitor Quisinostat.
- Performed RNA sequencing analysis on tumor samples.
- Analyzed immune cell populations (CD4+, FOXP3+, CD8+ T-cells, MDSCs).
Main Results:
- Targeting ΔNp63 inhibited tumor progression and metastasis in established TNBC models.
- ΔNp63 promotes myeloid-derived suppressor cell (MDSC) survival via tumor necrosis factor alpha.
- Loss of ΔNp63 altered MDSC properties including lipid metabolism and migration.
- Decreased ΔNp63 correlated with reduced CD4+ and FOXP3+ T-cells but increased CD8+ T-cells.
- Targeting ΔNp63 sensitized tumors to chemotherapy.
Conclusions:
- ΔNp63 plays a critical role in promoting TNBC progression and metastasis by reprogramming MDSC-mediated immunosuppression.
- Targeting ΔNp63 represents a promising strategy to overcome chemotherapy resistance in TNBC.
- Modulating ΔNp63 impacts the tumor immune microenvironment, offering new therapeutic avenues.
