Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that lacks hormone receptors. Current traditional treatments include chemotherapy and radiation therapy, which have limited efficacy in many patients with advanced TNBC, suggesting a need to find better drug targets. Recently, scientists have discovered a potential new target for treatment: a protein called ΔNp63. This protein appears to play an important role in helping cancer grow and spread, as well as in the ability of cancer cells to evade the body’s immune system. Understanding how ΔNp63 works could lead to more effective treatments for those battling this difficult 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 the survival and metabolism of myeloid-derived suppressor cells (MDSCs), providing a potential target for improved therapies for TNBC. 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 CRISPR-inducible knockdown 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. Decreased 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 triple-negative breast cancer. This highlights the potential benefits of targeting ΔNp63 in chemotherapy-resistant triple-negative breast cancer.”
The researchers employed several 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 decreased MDSC infiltration and fewer metastatic tumor cells in lymph nodes. Furthermore, RNA sequencing analysis indicated that loss of ΔNp63 impairs multiple properties of MDSCs, 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’s immune landscape, decreasing MDSC and regulatory T cell populations, while increasing cytotoxic T cells. These changes suggest that Quisinostat may enhance the anti-tumor immune response in TNBC.
Dr Chakrabarti said: “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 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 increased tumor suppression and reduced metastasis. This combination also reduced the number of MDSCs 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 to improve chemotherapy efficacy. By altering MDSC survival and function, ΔNp63 inhibition not only hampers tumor growth but also promotes a more robust anti-tumor immune response. These insights pave the way for the development of novel 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 She joined the Department of Surgery at the Miller School of Medicine in January 2022 as an Associate Professor. She is a tenured member of the Tumor Biology Program at Sylvester Cancer Center and is also Co-Director of the Surgical Breast Cancer Research Group. Prior to this position, she was an Adjunct Professor at the University of Pennsylvania for 6 years and received funding from the Department of Defense Breast Cancer Research, K22/NCI grants, NIH/NCI R01 grants, and several University of Pennsylvania grants. Her laboratory focuses on the role of immune and stromal cells, such as tumor macrophages, myeloid-derived suppressor cells, and natural killer cells, in the tumor microenvironment that shapes cancer stem cell fate during breast cancer relapse, recurrence, and metastasis. Her laboratory has developed a wide variety of mouse tumor models and uses human patient samples, organoid co-culture, PDX, patient explants, confocal microscopy, RNA sequencing, single cell sequencing, and other standard molecular and biochemical techniques to address these questions. The long-term goal of Chakrabarti's laboratory is to identify novel combination therapies targeting both immune and cancer cells to ultimately reduce patient mortality associated with aggressive breast cancer. Her research is currently funded by the NCI/NIH R01 program, the American Cancer Society Research and Breast Cancer Alliance Outstanding Award, and Breast Cancer Research Foundation grants.
Dr. Ukjin Kim is a postdoctoral associate at the Department of Surgery, University of Miami, Florida. He earned his BS and PhD in Veterinary Medicine (2016), and PhD (2020) from Seoul National University, South Korea. He had been a postdoctoral fellow at the Korea Institute of Medical and Radiological Sciences (KIRAMS), South Korea. His PhD research focused on redox homeostasis in prostate cancer to elucidate the paradoxical roles of reactive oxygen species depending on the stages of prostate cancer. During his first postdoctoral fellowship at KIRAMS, he reported that the P53/P21 complex is an important regulator of p53-dependent gene expression and tumor suppressor functions. Currently, his research interests include immuno-oncology, especially the function and metabolism of myeloid-derived suppressor cells (MDSCs) in triple-negative breast cancer (TNBC). Dr. Kim's research goal is to target MDSCs to inhibit the progression and metastasis of TNBC and develop a novel therapeutic strategy for immunotherapy-resistant TNBC.
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