Glioblastoma is the most common type of brain cancer and one of the most violent and deadly cancers in humans; the average life expectancy of glioblastoma patients is 12 to 15 months from the moment of detection. 

A new Tel Aviv University (TAU) study examined for the first time the development of a glioblastoma tumor in animal models with a normal immune system so as to best simulate the development of the tumor in humans. The study findings showed that there are immune system cells that – despite the fact that their main function is to attack and kill the cancer cells – actually act as “double agents” that increase and intensify the aggressiveness and threat of the tumor.

The study was led by Dr. Dinorah Friedmann-Morvinski of TAU’s Wise Faculty of Life Sciences and Sagol School of Neuroscience, her doctoral student Prerna Magod, together with Dr. Liat Rousso-Noori and Ignacio Mastandrea (also from the Faculty of Life Sciences) and other researchers from TAU’s Sackler Faculty of Medicine and the Weizmann Institute of Science in Rehovot. The study was published in the prestigious journal Cell Reports under the title “Exploring the longitudinal glioma microenvironment landscape uncovers reprogrammed pro-tumorigenic neutrophils in the bone marrow.”

The researchers wrote that usually, the scientific monitoring of the development of the cancerous tumor in animal models is carried out without an active immune system to enable the absorption and growth of cancer cells in the body. The disadvantage of this commonly-used model is that the immune system either does not exist or does not function properly; this prevents researchers from monitoring the interaction between it and the tumor cells.

The study, which was conducted in Friedmann-Morvinski’s lab, used a model that examined the development of cancer cells in animal models with functioning immune systems. This allowed the cancer to grow gradually to the point of the development of a massive tumor, which enabled the close monitoring of its development, and throughout the process of the interaction between the cancer cells and different immune system cells.

The researchers found that cells called neutrophils – immune system cells originating in the bone marrow whose purpose is to “swallow” or kill bacteria and fungi and fight the infections caused by them – play a critical role in interacting with the cancerous growth. “Neutrophils are the front-line soldiers of the immune system,” stated Friedmann-Morvinski. “When a tumor begins to develop, the neutrophils are among the first to mobilize and attack it in order to eliminate it.”

The researchers also found that the neutrophils remain near the tumor throughout its development and are continuously and consistently recruited from the bone marrow. The surprising thing that was discovered during this study is that the neutrophils “change sides:” While at first, with the onset of the initial tumor, the neutrophils fight it, over time the neutrophils recruited to the cancerous area begin to support its development.

“We learned that the neutrophils actually change their role,” said Friedmann-Morvinski. “They are mobilized by the tumor itself, and from being anti-cancerous, they become pro-cancerous; as a result, they aggravate the damage that the tumor itself creates.” 

In addition, the team found that the process by which the neutrophils change their properties can take place remotely, even before they progress towards the tumor itself.

“The study showed that the change in the properties of neutrophils takes place in the bone marrow itself – where there is no tumor at all: the cancerous tumor is located only in the brain and from there it succeeds in changing the properties of the cells it recruits,” added Friedmann-Morvinski. 

“The new findings of this study may also shed light on immunotherapeutic therapies, which have been gaining a lot of momentum in recent years. In one type of immunotherapy treatment, T cells are removed from the patient’s body, processed and returned to the body with increased healing abilities. One of the major problems today is that even these cells that have been sent to heal are suppressed and their actions stifled. If we know how to change the interaction between neutrophils and T cells so that they are not suppressed, this will have implications for the effectiveness of immunotherapy.”