Brain Tumors Incited by Blood Stem Cells

Glioblastomas are more inclined to dig in and spread out if they are egged on by hematopoietic stem cells. To “dig in,” the glioblastomas become more immunosuppressive. To “spread out,” they support the proliferation of cancer cells, promoting malignancy. The connection between immunosuppressive/malignant glioblastomas and blood stem cells was discovered by scientists affiliated with the German Cancer Consortium (DKTK). These scientists suggest that their work could open up new possibilities for developing more effective immunotherapies against glioblastomas, the most aggressive brain malignancies in adults.

Glioblastomas grow diffusely into healthy brain tissue. They defy the combination of surgery, radiotherapy, and chemotherapy, and they usually continue to grow unchecked. Even immunotherapies, which achieve good results in some cases in other types of cancer, have had no effect on these malignant brain tumors to date.

“Glioblastomas apparently create an environment that actively suppresses the immune response,” explained Björn Scheffler, a professor of translational oncology at the West German Tumor Center, University Hospital Essen/University of Duisburg-Essen. “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.”

Scheffler and Igor Cima, another DKTK-affiliated researcher at the West German Cancer Center, supervised a study that culminated in an article that recently appeared in Nature Communications. The article, titled “Tumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression,” indicates that in patients, the amount of tumor-associated hematopoietic stem and progenitor cells (HSPCs) in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes.

“We demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes,” the article’s authors wrote. “Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression, and display signatures of active cell cycle phases.”

In tissue samples of 217 glioblastomas, 86 WHO grade II and III astrocytomas, and 17 samples from healthy brain tissue, the DKTK researchers used computer-assisted transcription analyses to draw up profiles of the cellular composition. The tissue samples were taken directly from the resection margins—where remaining tumor cells and immune cells meet.

The team was able to distinguish between signals from 43 cell types, including 26 different types of immune cells. To their great surprise, the researchers discovered hematopoietic stem and precursor cells in all the malignant tumor samples, while this cell type was not found in healthy tissue samples.

“When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis,” the article’s authors continued. “In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1, and secretion of tumor promoting cytokines such as IL-6, IL-8, and CCL2, indicating concomitant support of both malignancy and immunosuppression.

These findings were even more surprising. That is, they suggested that the HSPCs have fatal characteristics: They suppress the immune system and at the same time stimulate tumor growth. When the researchers cultured the tumor-associated blood stem cells in the same petri dish as glioblastoma cells, cancer cell division increased. At the same time, the cells produced large amounts of the PD-L1 molecule, known as an “immune brake,” on their surface.

Tumor organoids—tiny tumors grown in a petri dish from the brain tumor cells of individual patients—reacted to the blood stem cells, too. In the presence of these cells, the cancer cells formed a network of cell processes that connects them. Only a few years ago, scientists from the DKFZ and Heidelberg University Hospital discovered that glioblastoma cells communicate using these connections and can thus protect themselves against treatment-related damage.

All these observations suggested that the blood stem cells found in glioblastomas have a negative impact on the course of disease. This was confirmed in a study of 159 glioblastoma patients for whom data were available on the clinical course of disease. In this group of patients, it was consistently observed that the more blood stem cells a tumor contained, the more immunosuppressive messengers were released and the more immunosuppressive markers the cancer cells formed—and the lower the overall survival of the patients was.

It was already known from research reports that the blood stem cells in bone marrow tend to mature into immunosuppressive cell types during differentiation in the course of cancer. It appears that they are programmed by the tumor to do so. Cima—who, like Scheffler, is also affiliated with the German Cancer Research Center (DKFZ) in Heidelberg—suspects that a similar phenomenon might be responsible for the observations in the glioblastoma-associated blood stem cells.

“We can now see,” he said, “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. Immunotherapies would then have a better chance of being effective against glioblastomas.”

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