Sex Differences Loom Large in Glioblastoma Development

Important sex differences are evident in many aspects of glioblastoma (GBM) — the most common and deadliest brain cancer — down to the cellular environment of the tumor. That was the central message delivered by Cleveland Clinic stem cell biologist Justin Lathia, PhD, at a symposium devoted to the topic at the Society of NeuroOncology annual meeting in November 2018. Such differences likely help explain the advantage that women have in terms of GBM incidence and prognosis, and these differences may provide important clues to developing more targeted and effective therapies.

“We have found sex differences everywhere we look — including at systemic, cellular and genetic levels,” says Dr. Lathia, a researcher with appointments in Cleveland Clinic’s Lerner Research Institute and Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center. “Sex differences are inherent drivers of glioblastoma incidence and survival.”

GBM: More frequent and deadlier in males

Dr. Lathia’s research group has devoted the past few years to identifying sex variations in GBM and studying underlying processes that may explain them.

In collaboration with other researchers, the group drew on large U.S. databases to find that GBM incidence is 60 percent higher in males than in females, with average annual age-adjusted rates of 4.0/100,000 versus 2.5/100,000, respectively. Females also have a significant survival advantage over males, with a median difference of up to 10 months (25.5 vs. 15 months) among patients with the most common mutation — isocitrate dehydrogenase 1/2 (IDH1/2) wild type — after adjusting for age at diagnosis, extent of resection and postsurgical Karnofsky performance status, a measure of functional impairment. Details of these epidemiological findings were published in Neuro-Oncology in February 2018.

Inherent immunological variations

Dr. Lathia points out the existence of fundamental baseline differences in the immune system between the sexes, with females having an overall heightened response. This phenomenon, which likely explains why women are more prone to develop autoimmune diseases, has important implications for immunotherapy.

Moreover, sex differences have been observed in the treatment of patients with GBM with corticosteroids, which are used to reduce the frequent complication of cerebral edema. These agents tend to have more pronounced immunosuppressive effects in males than in females.

Dr. Lathia’s group has also found sex differences in immune cell composition in the tumor microenvironment, specifically in myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, as well as in cell and junctional adhesion molecules, all of which are believed to play critical roles in cancer stem cell function and GBM progression (see previous Consult QD post on Dr. Lathia’s MDSC research).

Dr. Lathia explains that so far, GBM has proven resistant to even aggressive treatment with the conventional approaches of surgery, radiation and chemotherapy. “Having a good understanding of the immune system may be critical to treating GBM, as it offers promising new avenues of therapy,” he adds.

Surprising sex differences in microglia, chemotherapy, genetic mutations

Dr. Lathia reported on an interesting study from a group from Italy (Cell Rep. 2018;23:3501-3511) that found that microglia — myeloid cells in the central nervous system with multiple important protective functions against tumor growth and invasion — have different profiles of gene expression depending on whether they come from male or female rats. If female microglial cells are transplanted into male rat models of GBM, much smaller brain lesions develop than otherwise grow in males.

Female microglial cells have been shown by other investigators to be protective in stroke as well, according to Dr. Lathia, and he adds that his group has also found gender differences in cellular responses to chemotherapy.

Additionally, Dr. Lathia was part of a multicenter team that recently identified sex-specific variations in glioma-associated gene mutations (Neuro-Oncol. 2018 Aug 14 [Epub ahead of print]). The authors note that these findings provide additional evidence that differences in GBM risk likely have at least a partial genetic basis.

Figure. Imaging of growing glioblastoma tumors in the brains of living mice. We use advanced imaging technologies in living mice to follow the interactions between immune cells of the brain (green) and tumor cells (orange) — interactions in which we observe striking differences between males and females. Extensive and dynamic interactions can be recorded at the leading edge of a growing tumor (left), whereas at the core of the tumor (right) immune cells are gradually displaced and the tumor cells grow in high density. These imaging approaches allow us to revisit the same tumors on different days as the tumors grow, enabling detailed study of how the interactions evolve and the impact they may have on the rate of tumor growth and animal survival. Images courtesy of Dimitrios Davalos, PhD, Cleveland Clinic Department of Neurosciences.

Future steps

Dr. Lathia adds that recognizing the prominent role that sex plays at so many levels of GBM is now influencing his group’s study designs and data analyses. They are planning a large-scale project that will delve into the genetics, epigenetics and cell biology of GBM.

“We look forward to further elucidating sex differences and the role they may play in glioblastoma on the most basic level,” he observes. “A more thorough understanding of the nuances of the underlying physiology may make a big difference in making headway for therapeutics.”

These investigations of sex differences in GBM are a collaborative effort between Dr. Lathia and Jill Barnholtz-Sloan (Case Comprehensive Cancer Center, Cleveland), James Connor (Penn State University, Hershey, Pennsylvania), Joshua Rubin (Washington University, St. Louis) and Michael Berens (The Translational Genomics Research Institute, Phoenix).