March 2, 2024

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Breakthrough in Brain Metastasis Cancer Treatment: New Target Identified – CD276

Breakthrough in Brain Metastasis Cancer Treatment: New Target Identified – CD276



Breakthrough in Brain Metastasis Cancer Treatment: New Target Identified – CD276

Brain metastasis (BrM) is the most common intracranial tumor, originating primarily from lung cancer (40%–50%), breast cancer (15%–25%), and melanoma (5%–20%). Despite treatments such as molecular targeted therapy, immunotherapy, stereotactic radiotherapy, or traditional surgery, the median survival is only 5-10 months, emphasizing the need for a deeper understanding of BrM biology to develop more effective treatments.

The vascular system plays a crucial role in regulating the metastatic spread and progression of BrM tumor microenvironment (TME). However, the heterogeneity of the key components (endothelial cells, mural cells) of BrM blood vessels is still poorly understood.

On January 18, 2024, researchers from the University of Lausanne in Switzerland published a study titled “Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms” in the Cancer Cell journal.

Breakthrough in Brain Metastasis Cancer Treatment: New Target Identified – CD276

Recent analysis of samples from BrM patients revealed the significance of the brain tumor microenvironment (TME) in regulating the progression of primary and metastatic malignant brain tumors. The immense complexity of the TME in BrM is being unveiled, with a focus on the immune cell landscape. However, a comprehensive map of the vascular cavities in human BrM is currently lacking.

The blood-brain barrier (BBB) consists of endothelial cells (EC), mural cells, astrocyte end-feet, and closely associated pericytes. While the tight connections formed by endothelial cells act as a selective barrier, allowing necessary nutrients to enter and protecting the brain from pathogens and toxic substances, metastatic cancer cells can breach the BBB through various mechanisms. After settling in the brain, these cancer cells alter the vascular system, forming a tumor barrier. Though this abnormal vascular system may allow peripheral immune cell infiltration, including CD8+ T cells, it does not induce a lasting immune response.

In this study, the research team conducted in-depth analyses of key components of the brain tumor vascular system. They performed single-cell RNA sequencing, bulk RNA sequencing, and spatial TME imaging analysis on vascular cells from human and mouse BrM and non-tumor brain samples. They also conducted preclinical studies using a BrM model to address questions such as the heterogeneity of endothelial and mural cells in BrM, structural and molecular changes associated with BrM in these vascular components, and how to target the BrM vascular system in treatment.

The analysis revealed significant differences in the gene expression patterns of endothelial cells and mural cells in BrM compared to cells from non-cancerous brain tissue. This suggests various distortions in the brain tumor blood vessels, including issues with cell-to-cell connections and adhesion in endothelial cells and mural cells, reflecting the well-known “leakiness” of tumor vessels. These changes suppress anti-tumor immune responses or induce T-cell suicide targeting cancer cells.

Integrating the experimental data with mouse models, the research team established a platform to discover treatment targets for the vascular system in BrM. They identified an immune inhibitory molecule – CD276, which is particularly abundant in endothelial cells and mural cells of brain metastases. CD276 emerges as a promising target for cancer immunotherapy, known to inhibit T-cell proliferation, support cancer cell immune escape, and correlate with poor prognosis in cancer patients.

The team further confirmed that antibodies targeting CD276 could inhibit the growth of brain tumors in a mouse model of breast cancer and significantly extend their survival. Additionally, this treatment induced molecular-level changes in vascular structure and promoted the entry of cytotoxic T cells into the tumor.

The researchers stated that besides identifying CD276 as a potential therapeutic target for brain metastasis, this study provides crucial insights into the complex interactions between the vascular system, immune cells, and cancer cells, with significant translational implications for developing interventions against brain metastasis.

Paper Link: Cancer Cell Full Text


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