Blood Stem Cells Key to Glioblastoma Proliferation and Immunosuppression

Blood Stem Cells Key to Glioblastoma Proliferation and Immunosuppression

New research conducted by scientists at the German Cancer Consortium (DKTK) has shown hematopoietic stem cells make brain tumors more aggressive. The stem cells simultaneously promote division of cancer cells while supressing the immune response against the tumors.

Glioblastomas are a highly aggressive form of brain cancer. Glioblastomas are resistant to all methods used to treat cancer. Surgery is not usually an option, as the tumors are diffuse throughout the brain, which makes it impossible to remove them all and chemotherapy, radiotherapy, and immunotherapies are not effective.

Glioblastomas are relatively rare, accounting for around 1 in 10,000 cancer diagnoses, but they are the most common form of brain cancer, accounting for around 16% of all primary brain tumors. With a lack of treatment options, glioblastomas usually grow unchecked and are almost always fatal.

“Glioblastomas apparently create an environment that actively suppresses the immune response,” said Björn Scheffler, DKTK Professor of Translational Oncology at the West German Tumor Center in Essen, partner site Essen/Düsseldorf. “They produce immunosuppressive messengers, and in the immediate environment of the tumors we find certain types of immune cells that specifically suppress the immune defense.”

Prior to the study, little was known about the variety of immune cells in the microenvironment of glioblastomas. Scheffler and the other DKTK researchers set about studying the cellular composition of glioblastomas, as it was believed critical to understanding and overcoming immunosuppression to conventional cancer therapies.

The researchers studied tissue samples taken from 217 glioblastomas, 86 WHO grade II and III astrocytes, and 17 healthy brain tissue samples, using computer-aided transcription analyses to create profiles of cellular composition. The tissue samples were taken from the resection margins where immune cells and tumors meet.

The researchers were able to identify the signals between 43 different cell types, including 26 different types of immune cell. The researchers discovered hematopoietic stem and precursor cells (HSPCs) were present in all the malignant tumor samples but did not find those cell types in any of the healthy tissue samples. This is the first time that blood stem cells of glioblastomas have been described.

The researchers demonstrated that when glioblastoma cells are cultured in the same petri dish as tumor-associated blood stem cells, cell division increased and the glioblastoma cells produced large amounts of a molecule called PD-L1 on their surface, which suppresses the immune response. The researchers also found that tumor organoids reacted in the same way to the blood stem cells and formed a network of cell processes that connects them and helps to protect them against treatment-related damage.

A study was conducted on 159 glioblastoma patients, which showed the more blood stem cells were present in the tumor, the more immunosuppressive messengers were released, the more immunosuppressive markers formed in the cancer stem cells, and the lower the chances of patient survival were.

Previous research had shown that blood stem cells in the bone marrow mature into immunosuppressive cell types during differentiation during the course of cancer, but it is now known that it is the tumor that programs them to do so.

“We can now see an opportunity to intervene in order to modify the differentiation process of the glioma-associated blood stem cells, for example, through particular cell messengers, and hence prevent the immune system from being blocked as a result of the tumor,” said DKTK-affiliated researcher Igor Cima. “Immunotherapies would then have a better chance of being effective against glioblastomas.”

You can read more about the study in the paper – Tumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression – which was recently published in Nature Communications. DOI: 10.1038/s41467-021-23995-z