Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that lacks hormonal receptors.. Current traditional treatments include chemo and radio therapy, which have limited efficacy in several advanced TNBC patients, suggesting need to find better drug targets. Recently, scientists have discovered a new potential target for treatment: a protein called ΔNp63. This protein appears to play a significant role in helping the cancer grow and spread, as well as in the cancer cells’ ability to evade the body’s immune system. Understanding how ΔNp63 works could lead to more effective treatments for those battling this tough cancer.
A team of researchers led by Dr. Rumela Chakrabarti along with Dr. Ukjin Kim and Javier Maiz from the University of Miami, and Dr. Rahul Debnath, Joshua Rico, and Dr. Mario Blanco from the University of Pennsylvania, along with Professor Satrajit Sinha from The State University of New York, has shed light on the critical role of ΔNp63 in the progression and treatment of TNBC. The study focuses on how ΔNp63 influences myeloid-derived suppressor cell (MDSC) survival and metabolism, providing a potential target for improving TNBC therapies. Their findings are published in the peer-reviewed journal iScience.
The study demonstrates that ΔNp63 is highly expressed in TNBC tumors and plays a pivotal role in tumor progression and metastasis. Targeting ΔNp63 using both inducible CRISPR knockout techniques and the histone deacetylase (HDAC) inhibitor Quisinostat resulted in reduced tumor growth and metastasis. The researchers found that ΔNp63 promotes MDSC survival through tumor necrosis factor alpha (TNF-α), reshaping the tumor microenvironment by altering immune cell populations. Decreasing ΔNp63 levels led to a reduction in CD4+ and FOXP3+ T-cells while increasing CD8+ T-cells, suggesting a shift from immune evasion to immune surveillance.
Dr. Chakrabarti explained, “Our research shows that ΔNp63 reprograms the immunosuppressive functions of MDSCs in TNBC. This highlights the potential benefits of targeting ΔNp63 in chemotherapy-resistant TNBC.”
The researchers employed various models, including genetically engineered mouse models (GEMM) and syngeneic TNBC allografts, to study the effects of ΔNp63 inhibition on established tumors. They observed that conditional loss of ΔNp63 in spontaneous TNBC tumors resulted in decreased tumor growth and metastasis. Immunostaining revealed reduced MDSC infiltration and fewer metastatic tumor cells in lymph nodes. Moreover, RNA sequencing analysis indicated that loss of ΔNp63 affects multiple MDSC properties, such as lipid metabolism, chemotaxis, and migration.
In addition to genetic approaches, the team explored pharmacological inhibition of ΔNp63 using Quisinostat. This HDAC inhibitor not only reduced ΔNp63 protein levels but also significantly inhibited TNBC tumor progression and metastasis. The treatment altered the tumor immune landscape, decreasing MDSC and regulatory T-cell populations while increasing cytotoxic T-cells. These changes suggest that Quisinostat can enhance the anti-tumor immune response in TNBC.
Dr. Chakrabarti stated, “Targeting ΔNp63 with Quisinostat not only suppresses tumor growth but also modifies the immune environment to favor anti-tumor immunity. This dual action makes it a promising candidate for combination therapies.”
The study’s findings underscore the potential of targeting ΔNp63 in TNBC to improve chemotherapy outcomes. The researchers demonstrated that combining ΔNp63 inhibition with conventional chemotherapy sensitizes TNBC tumors to treatment, leading to greater tumor suppression and reduced metastasis. This combination also decreased MDSC numbers and increased their apoptosis, indicating a compromised immunosuppressive environment.
In summary, the research by Dr. Chakrabarti and her team provides compelling evidence that ΔNp63 is a crucial regulator of TNBC progression and a viable target for enhancing chemotherapy efficacy. By disrupting the survival and function of MDSCs, ΔNp63 inhibition not only hampers tumor growth but also promotes a more robust anti-tumor immune response. These insights pave the way for developing new therapeutic strategies to combat the aggressive nature of TNBC.
Journal Reference
Kim, U., Debnath, R., Maiz, J. E., Rico, J., Sinha, S., Blanco, M. A., & Chakrabarti, R. (2024). ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer. iScience, 27, 109366. DOI: https://doi.org/10.1016/j.isci.2024.109366
About the Authors
Dr. Rumela Chakrabarti joined Department of Surgery in Miller School of Medicine in January 2022 as an Associate professor. She is a full member of Tumor biology program in Sylvester Cancer Center and is also a co-director of Surgical Breast cancer research group. Before this position, she was an Assistant Professor in University of Pennsylvania for 6 years and was funded by DoD Breast Cancer Research, K22/NCI grants, NIH/NCI R01 and several University of Pennsylvania grants. Her laboratory on the role of immune and stromal cells such as tumor macrophages, myeloid derived suppressor cells and Natural Killer cells in tumor microenvironment shaping the fate of cancer stem cells during relapse, recurrence and metastasis of breast cancer. Her laboratory has developed a wide variety mouse tumor model and utilizes human patients’ samples, organoid co-culture, PDX, Patient explants, confocal microscopy, RNA-sequencing, single cell sequencing besides other standard molecular and biochemical techniques to address these questions. Long-term goal of Chakrabarti lab is to identify novel combination therapies targeting both immune and cancer cells to ultimately decrease patient mortality associated with aggressive breast cancer. Her research is currently funded by NCI/NIH R01, American cancer Society Research and Breast Cancer Alliance Exceptional Award and Breast Cancer Research Foundation grants.
Dr. Ukjin Kim is a Postdoctoral Associate of Department of Surgery of University of Miami, Florida. He got his bachelor’s degree and Doctor of Veterinary medicine (2016), and doctor’s degree (2020) in Seoul National University, South Korea. He had been a postdoctoral fellow at Korea Institute of Radiological & Medical Sciences (KIRAMS), South Korea. His PhD research was focused on redox homeostasis in prostate cancer to elucidate paradoxical roles of reactive oxygen species depending on the stages of prostate cancer. During his first postdoctoral fellowship at KIRAMS, he reported P53/P21 complex as important regulator of p53-dependent gene expression and tumor suppressive functions. Currently, his research interests include immuno-oncology, especially function and metabolism of myeloid-derived suppressor cells (MDSCs) in triple-negative breast cancer (TNBC). Dr. Kim’s research goal is targeting MDSCs to inhibit progression and metastasis of TNBC and developing novel therapeutic strategy for immunotherapy-resistant TNBC.
