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“Tumour cells thrive by adapting to the many signals in a complex microenvironment,” Associate Professor Mantamadiotis said.

“To adapt, cancer cells send a range of signals to neighbouring cells, including immune cells, and also respond to other factors, like collagen, to ‘tame’ their microenvironment, which allows tumours to thrive.”

In a study published in Cellular Oncology, the team, in collaboration with researchers from the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital’s Department of Neurosurgery, made two important discoveries, using spatial biology to map the tumour tissue architecture to understand how and where immune cells traffic to, and how cancer cells alter their signals in response to their surrounding  microenvironment.

“Surprisingly, we found the presence of excessive collagen in glioblastoma – one of the most aggressive and fastest growing types of brain cancer,” explained Marija Dinevska, co-author of the study and PhD student in the Mantamadiotis Lab.

“While we expected to see collagen in other types of cancer, like pancreatic or breast cancer, it wasn’t something I expected to see at such high levels in brain tumours. This is an important discovery because collagen can influence cancer cell signalling and activation, and consequently influence how the cells behave.”

Researchers also showed that, while there is little cell infiltration in less malignant brain tumour tissue, more aggressive brain tumours exhibit not only an increase in the number of tumour infiltrating immune cells, but also enhanced immune cell activation.

“While high immune cell activation is usually good news, we discovered that most T-cells, the white blood cells that are key to anti-tumour immune responses, become trapped in the collagen around blood vessels, and are incapable of moving deeper where they can kill the cancer cells,” explained Samuel Widodo, co-author of the study and PhD student in the Mantamadiotis Lab.

The team also observed that a larger type of immune cell, the macrophages[¹] are able to migrate from the blood vessels, through the collagen and penetrate deep into cancer cell-rich regions. However, once there, they become immunosuppressive and actually help the tumour cells grow and invade into surrounding healthy brain tissue.

Malignant brain cancers are amongst the most difficult to treat cancers, affecting people at any age. For the most common and deadly type of brain cancer, glioblastoma, prognosis is very poor and treatment options limited. Unlocking the mechanisms of the immunobiology of brain tumours is a step towards developing better treatment for patients.

“Overall, our research suggests that immunotherapies relying on T cells alone may be limited, and that cellular immunotherapies using macrophages may be more effective for brain cancer,” said Associate Professor Mantamadiotis.

“Targeting the tumour collagen, in combination with inhibiting specific cell signalling activation will be critical to designing personalised cancer therapy, including immunotherapy tailored for patients with brain cancer.”

Peer review: Cellular Oncology https://doi.org/10.1007/s13402-022-00763-9
Funding: CASS Foundation