Pioneering studies of scientists from the Nencki Institute have allowed the identification of diverse types of macrophages accumulating in malignant gliomas. Macrophages are the guardian cells of the immune system which turn “bad”, and actively support glioma growth. Understanding the origin and function of tumor infiltrating macrophages may allow “turning-off” the most aggressive cells and restore antitumor immunity.

Glioblastoma is one of the most aggressive and incurable primary brain tumors in adults. Patients live on average for 14 months from the initial diagnosis. Current glioblastoma treatment involves tumor resection, chemo and radiotherapy, but will only extend the patients' life by several months – says prof. Bożena Kamińska from the Laboratory of Molecular Neurobiology, the Nencki Institute of Experimental Biology in Warsaw.

The Kamińska’s group explores glioma biology, in the search for novel therapeutic targets. In the latest “Nature Communications”, researchers publish their work unraveling the types of macrophages that accumulate in gliomas, and describe how tumors change their functions. For the first time in Poland, scientists applied the newest method of transcriptome sequencing with single cell resolution (scRNA-seq). Transcriptome carries information about all the processes that are happening within the cell. It changes in response to the external environment, and adjusts the physiological reactions to new situations. The researchers think that a precise dissection of the identities of immune cells in gliomas may help to develop a targeted therapy that would allow “turning off” specific, tumor supporting cells, and restore their ability to fight the tumor.

By analyzing transcriptome at the single-cell level, it is possible to precisely divide cells into distinct subpopulations that perform unique roles. This dissection was not possible, as there were no markers to characterize functions of specific immune cells accumulating in gliomas.

Brain resident macrophages (microglia) migrate towards and are activated by a tumor; some macrophages come from the peripheral blood. – We think that both tumor cells, and tumor-activated microglia, produce substances that attract monocytes from the blood. Monocytes migrate to the brain, and in the tumor microenvironment, differentiate into pro-tumor macrophages that block the anti-tumor immune responses – says Natalia Ochocka, one of the main authors. As a result, T lymphocytes do not migrate, and their antitumor action is blocked.

– In gliomas, we find mainly two types of immune cells that have different origin and function, but both are reprogrammed into cells that support tumor progression – says prof. Kamińska.

In this work, researchers demonstrate that macrophages emerging from the peripheral monocytes localize in the center of the tumor, while in the tumor surroundings, we find mainly microglia. It is a specialization, which indicates that if those cells localize in different regions, they may have a distinct role in supporting the tumor growth – says Natalia Ochocka.

She believes the findings might be a step forward in the development of new, more effective methods for glioma treatment. By targeting specific macrophage populations, glioma growth could be slowed down, and immune cells of the patient could be reactivated to fight the tumor.

Moreover, the findings in “Nature Communications” indicate that the tumor microenvironment varies in different sexes. Microglia in male mice respond stronger to the tumor presence than in the female. Similar sex-dependent changes in gene expression were found in humans gliomas. Those differences do not depend on hormonal status , as glioblastomas develop in elderly people, that is in postmenopausal women. In men, glioblastoma is twice as common as in women, but interestingly, men show better outcomes from cancer immunotherapy that stimulates the patient’s own immune responses. Those differences could be due to distinct microglia responses in males and females.