Researchers identify immunotherapy targets to fight glioblastoma

S100A4 (green), a protein-positive immune cell, may be a potential therapeutic target to restore the immune cells’ antitumor effects on glioblastoma.Credits: Houston Methodist

Researchers at Houston Methodists have identified genetic and molecular fingerprints of various cancers and immune cells of glioblastoma, the most deadly and most common type of brain tumor in adults.

Detailed molecular analysis of over 200,000 single cells revealed a protein called S100A4. this is, Immune cells Otherwise towards glioblastoma, which tricked the immune system into protecting it.

A study entitled “Single-cell analysis of human gliomas and immune cells identifies S100A4 as a target for immunotherapy” was recently published. Nature CommunicationsAnd search for targeted therapies for heterogeneous tumors, including different types of tumors. Normal cells It is mixed in a single mass. These heterogeneous cancers are notorious for being difficult to manage because effective treatments for one group of tumor cells may not be completely effective in another.

About 48% of all primary malignant brain tumors are glioblastoma, and more than 10,000 people die from the disease each year in the United States.Highly invasive brain cancer cell It penetrates extensively into the brain and makes surgical resection a huge challenge. In addition to the complexity of the disease, the cancer is capable of rapidly mutating, so even in different parts of the brain of the same patient, glioblastoma embraces a mosaic of cancer cell types, making a major setback in targeted therapies. Bring.

As with most illnesses that affect the brain, Blood-brain barrier Drug delivery has another challenge. In glioblastoma, the blood-brain barrier weakens, allowing peripheral immune cells to penetrate the central nervous system. However, curiously, glioblastoma tends to promote those malignancies by selectively attracting most of the immune cells that invade the tumor or turning them into immunosuppressive cells.

“Currently, many immunotherapies target the reactivation of effector T cells, which are important for attacking and eliminating cancer cells, but in gliuloblastoma, infiltration of effector T cells does. Is very low, “says Dr. Kyuson Yun. , Senior Author of Studies at the Houston Institute of Methodists and Associate Professor of Neurology at the Houston Institute of Methodists. “Instead, glioblastoma has an excess of immunosuppressive bone marrow cells.”

To investigate complex immune cancer cell interactions, researchers performed comprehensive gene profiling of different cell types in 44 samples of glioblastoma from 18 patients. For each patient, they analyzed glioblastoma tissue in different parts of the brain tumor to gain insight into the cancer heterogeneity within each patient. We then performed a high-throughput single-cell RNA sequence to catalog individual cells based on gene expression in various molecules.

Grouping cells based on their molecular profile, researchers found that intra-patient and patient-wide glioblastoma cells were grouped into nine groups based on cell status, independent of specific mutations in individual cells. I found that it can be classified. They further identified nine subtypes of glioblastoma bone marrow cells. It contains microglia, the primary immune cells of the brain, and is associated with improved patient outcomes. Tumors were also immunosuppressive and filled with bone marrow-derived macrophages and regulatory T cells (Tregs) that were associated with worse patient outcomes.

Therefore, the researchers turned their attention to identifying molecules that are activated in immunosuppressive T cells and myeloid cells. Their strategy was to selectively target “bad” immune cells that conserve “good” immune cells associated with better survival and promote tumor growth and immune avoidance. They found that the S100A4 regulator protein was produced and secreted by glioblastoma cancer cells, immunosuppressive T cells, and bone marrow-derived bone marrow cells.

Yun said her team plans to develop an antibody drug that targets this S100A4 protein to loosen its tight grip on regulatory T cells and bone marrow-derived macrophages in glioblastoma. .. In addition, they plan to develop small molecules that can enter the nucleus of cancer cells and inhibit the function of the S100A4 protein in glioblastoma stem cells.

“Currently, there is a lack of understanding of which bone marrow cell type promotes, so the treatment employs a sledgehammer approach. Glioblastoma Which is growth and what impedes it, “Yun said. ‚ÄúSingle cell sequencing has allowed us to define heterologous bone marrow cell types and identify molecular properties of immune cells that promote or suppress. Tumor growth As a result, we were able to selectively manipulate immunosuppressive cells to restore the flight effect of the tumor. Immune system.. “

In the coming years, she says, single-cell datasets like this one will dramatically change the understanding of human cancer and guide efforts towards the development of a new generation of anti-cancer drugs, especially for immunotherapy. I added that.

Status of innate immunity in tumors of patients with glioblastoma

For more information:
Single-cell analysis of Nourhan Abdelfattah et al, human glioma and immune cells identifies S100A4 as a target for immunotherapy. Nature Communications (2022). DOI: 10.1038 / s41467-022-28372-y

Provided by
Houston Methodist

Quote: Researchers fight glioblastoma (April 5, 2022) obtained on April 5, 2022 from https: // Identify immunotherapy targets for

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Researchers identify immunotherapy targets to fight glioblastoma

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