Glioblastoma ‘ecosystem’ redefined for more effective immunotherapy trials

A research team has revealed the intrinsic gene expression patterns of glioblastoma (GBM) tumours, insights that could drive more effective treatments for GBM, the most common and deadly malignant primary brain tumours in adults.

Jackson Laboratory (JAX) Professor Roel Verhaak, Ph.D., is the senior author of a paper showing tumour gene expression patterns distinct from those of the surrounding immune cells, and characterizing the effects of chemotherapy and radiation treatments.

Verhaak was the first author of a 2010 paper that established four subclasses of GBM — proneural, mesenchymal, neural and classical — based on molecular markers found in patient tumours. That paper was widely influential in the glioblastoma research field, observes Verhaak. “However, these four subtypes have not translated into differential treatment strategies. Every glioblastoma patient receives essentially the same treatment. We hope that our latest work will improve understanding of how to optimally stratify patients, another step towards precision medicine and more targeted, effective treatments.”

The cells that surround a tumour are known as its microenvironment, usually consisting of immune cells, supporting cells and other normal cells. Tumours donated to tissue banks consist of a mixture of microenvironment cells and cancer cells.

In the new paper, the research team isolated the intrinsic gene expression of 364 GBM tumours and observed the impact of the standard cancer treatment regimens of temozolomide and radiation on that expression after subtracting out the effects of therapy on the tumour-associated non-cancer cells.

“By separating out the contributions of the microenvironment, we developed a much clearer picture of the ‘ecosystem’ of hundreds of tumours,” Verhaak says. “We determined what types of cells are in the microenvironment and what their contributions are, and also assessed how treatment affects the microenvironment as well as the tumour cells themselves.”

Through this approach, the researchers found that the molecular markers defining the neural subtype of GBM was actually ascribed by the presence of normal neural tissue in the tumour margin, thus not representing a true tumour subtype.

By studying gene expression patterns in glioblastomas after treatment, their analysis also revealed that the presence of macrophages correlates with poorer outcomes for GBM patients receiving radiation therapy, and that tumours with a relatively high number of point mutations have an increased number of positive T cells, indicating they could respond to a kind of immunotherapy known as checkpoint inhibitors.

The resulting gene expression datasets, which are publicly available to researchers, provide comprehensive profiles of glioblastoma characteristics to more accurately guide immunotherapy trials.

Jackson Laboratory