Glioblastoma Induces ‘Stockholm Syndrome’ to Subvert Body’s Defences
Glioblastoma, an aggressive form of brain cancer, has been found to corrupt immune cells and make the tumour harder to treat.
Most people diagnosed with glioblastoma die in a short period of time after their diagnosis, but some glioblastoma patients see great benefits from chemotherapy and survive beyond expectations. Researchers at the University of Minnesota have revealed the reason for this in a new study published in the Proceedings of the National Academy of Sciences.
“Deciphering the molecular underpinning of these exceptional responses may hold the key to transforming the hope for miracles into the reality of an expected cure for glioblastoma patients,” said lead author Clark C Chen, MD, PhD, Lyle French Chair in Neurosurgery and head of the Department of Neurosurgery at the University of Minnesota Medical School.
Examining the gene expression profiles of glioblastoma samples from approximately 900 glioblastoma patients, the researchers sought to identify unique features associated with exceptional responders, defined as glioblastoma patients who survive more than two years after treatment.
“We utilized different state-of-the-art analytics to study these samples, including methods innovated by Dr. Aaron Sarver, a member of the University of Minnesota Institute of Health Informatics. Impressively, these analytics converged on a single observation, a paucity of microglia and macrophages,” Dr Chen said.
Specialised immune cells, microglia and macrophages act as scavengers, spotting and removing out-of-place cells in healthy brains. They travel to abnormal cancer cell sites to mount a defence, and can form over half the cells in a glioblastoma sample.
“If microglia and macrophages normally fend off cancer cells, more of them should allow the body to better fend off the tumor. So, we expected to see more of them in the exceptional responders; however, we found the contrary,” said Jun Ma, a researcher in the Department of Neurosurgery at the U of M Medical School and a co-first author of this study.
In order to resolve this paradox, the research team then demonstrated that glioblastoma cells can recondition the surrounding microglia and macrophages, corrupting their normal anticancer functions. Where they once fought off cancer growths, these immune cells are now re-programmed by glioblastoma cells to promote tumour growth.
“It is frightening to consider the possibility that cancer cells can ‘brainwash’ our own immune cells and convert them from cells that fight cancer to cells that promote cancer,” said Judith Varner, a co-senior author of the study and professor of pathology at the University of California, San Diego. “Fortunately, we have figured out how glioblastoma cells subvert our immune system and can now reverse this cellular version of the ‘Stockholm syndrome.'”
Stockholm syndrome is characterised as when a captive begins to identify closely with their captors, as well as with their agenda and demands, however there is little evidence for it being a true psychological phenomenon.
A protein known as phosphoinositide-3-kinase gamma isoform (PI3Kγ) could hold the key to cure this cellular “Stockholm syndrome” and possibly glioblastoma. This protein, when activated, is the switch that corrupts their anti-cancer role. Having studied this process for many years, Varner has pioneered drugs that restore the anti-tumour activities of microglia and macrophages.
“In our animal glioblastoma models, treatment with drugs targeting PI3Kγ consistently resulted in impressively durable responses to chemotherapy,” Chen said. “We are eager to translate these findings into a human trial, with the hope of transforming every glioblastoma patient into an exceptional responder.”
Source: Medical Xpress
Journal information: Jie Li et al, PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2009290118
