Glioblastoma ‘ecosystem’ redefined for more effective immunotherapy trials

Candy diagram

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

Jackson Laboratory (JAX) Professor Roel Verhaak, Ph.D., is the senior author of a paper published in Cancer Cell showing tumor 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 landmark 2010 paper in Cancer Cell that established four subclasses of GBM — proneural, mesenchymal, neural and classical — based on molecular markers found in patient tumors. 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 tumor are known as its microenvironment, usually consisting of immune cells, supporting cells and other normal cells. Tumors 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 pattern of 364 GBM tumors and observed the impact of the standard cancer treatment regimens of temozolomide and radiation on the gene expression patterns on both the remaining tumor and non-tumor cells, after subtracting out the effects of therapy on the tumor-associated non-cancer cells.

“By separating out the contributions of the microenvironment, we developed a much clearer picture of the ‘ecosystem’ of hundreds of tumors,” 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 tumor cells themselves.”

Through this approach, the researchers also found that the molecular markers previously defining the neural subtype of GBM was actually ascribed to the presence of normal neural tissue in the tumor margin, thus not characteristic of the actual tumor 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 tumors with a relatively high number of point mutations have an increased number of positive (CD8+) 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.

JAX Senior Research Scientist Hoon Kim, Ph.D., M.Sc., and Postdoctoral Associate Floris Barthel, M.D., are coauthors of the paper. Verhaak’s collaborators include Eric P. Sulman of The University of Texas MD Anderson Cancer Center, Houston, Texas, and Do-Hyun Nam of Samsung Medical Center, Sungkyunkwan University and Sungkyunkwan University School of Medicine, Seoul, Korea.

Support for this research came from the National Institutes of Health (grants P50 CA127001, R01 CA190121, P50 CA097257, RO1 CA120813, P30CA16672 and P30CA034196), the Cancer Prevention & Research Institute of Texas, University Cancer Foundation via the University of Texas MD Anderson Cancer Center University Cancer Foundation, the National Brain Tumor Association Defeat GBM project, National Brain Tumor Association Oligo Research Fund, the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare of the Republic of Korea, the Seve Ballesteros Foundation and the American Cancer Society.



Wang et al.: Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. Cancer Cell, July 10, 2017, 10.1016/j.ccell.2017.06.003