by Researchers at Ludwig Cancer Research have conducted a comprehensive study analyzing the cellular and molecular components of the blood vessels that supply brain metastases of melanoma, lung, and breast cancers. The study has shed light on how these blood vessels contribute to the growth and immune evasion of tumors. In addition, the researchers have developed a platform to identify potential vulnerabilities in the blood vessels of brain metastases, leading to the identification of a protein called CD276 as a target. Inhibiting CD276 with antibodies significantly prolonged the survival of mice with brain metastases of breast cancer.
The findings of this study are significant in deepening our understanding of the intricate interactions between blood vessels, immune cells, and cancer cells within the brain. This knowledge could pave the way for the development of more effective therapies targeting brain tumors, which currently have a poor prognosis with patients surviving less than a year after diagnosis.
Solid tumors, including brain metastases, rely on noncancerous cells to support their growth and survival. This includes immune cells, fibroblasts, and the cellular components of new blood vessels. The study by the Ludwig Cancer Research team focused on analyzing the vasculature of brain tumors, which is responsible for establishing a blood-tumor barrier to support and protect the tumors.
To understand this process, the researchers extensively analyzed the molecular features and gene expression patterns of the cells forming the blood-brain barrier in noncancerous brain tissue and brain tumor samples from patients with melanoma, lung, and breast cancers. They found significant differences in gene expression patterns between the cells in tumor blood vessels and those in noncancerous brain tissue. These differences indicated abnormalities in tumor vessels, including problems with cell adhesion and leakiness. The cells in tumor blood vessels also interacted more with certain immune cell subsets.
The study findings were validated using advanced imaging methods and mouse models of brain metastasis. The researchers discovered that the endothelial cells and mural cells of blood vessels regulate the movement of immune cells into brain metastases. They also identified changes in molecular signaling pathways in these cell types that suppress anti-tumor immune responses or induce T cell death.
One molecule of particular interest was CD276, which was found to be abundant in the blood vessels of brain metastases. CD276 is known for inhibiting T cell proliferation and supporting immune evasion by cancer cells. In the mouse model of breast cancer brain metastases, the researchers found that antibodies targeting CD276 inhibited tumor growth, prolonged survival, and altered the vasculature at the molecular level. The treatment also increased the infiltration of killer T cells into tumors.
In addition to identifying CD276 as a potential therapeutic target for brain metastases, the researchers identified other potential targets for drug development. They also validated a reliable model system for testing these targets before further development. This study brings us closer to developing more effective therapies for brain tumors by targeting the specific vulnerabilities of the tumor blood vessels.
Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
