Northwestern Medicine scientists have uncovered a biological mechanism that helps explain why most patients with glioblastoma fail to respond to immunotherapy, according to a study published in Nature Communications.
Glioblastoma (GBM) remains one of the deadliest forms of cancer, with few effective treatment options once tumors recur. While immune checkpoint inhibitors have transformed care for several cancer types, most patients with GBM don’t respond to the therapy, and investigators have struggled to understand why only some patients experience lasting responses.
“Mostly, we have been disappointed with the results. Some patients didn’t do well. But, occasionally we had some remarkable success, and we just didn’t know why,” said Adam M. Sonabend, MD, associate professor of Neurological Surgery, who was senior author of the study.
To answer those questions, the investigators conducted in vivo CRISPR/Cas9 screens in a mouse model of glioma. Among hundreds of targets, components of the RAF-MEK-ERK signaling cascade emerged as the strongest regulators of tumor susceptibility to anti-PD-1 therapy and CD8+ T-cell recognition.
The findings suggest that MAPK/ERK activity enhances immune recognition of tumors, increases T-cell infiltration, and stimulates inflammatory signaling programs that support anti-tumor immunity.
The new study builds on years of prior research examining the role of MAPK signaling in glioblastoma immunotherapy outcomes. Earlier studies from the Sonabend laboratory revealed that rare mutations in the BRAF and PTPN11 genes — which both activate the MAPK pathway — appeared disproportionately among patients who responded to immunotherapy. Subsequent studies found that elevated MAPK pathway activity was correlated with longer survival following immunotherapy.
“This latest study confirms what I suspected, which is that MAP kinase signaling in the tumor, which is a very common oncogenic pathway, somehow, as a side product, ends up modulating the susceptibility to immunotherapy of these tumors,” said Sonabend, who is also director of Translational Neurooncology at Northwestern Memorial Hospital.
Next, the team then demonstrated that increasing ERK activation improved responses to both anti-PD-1 and anti-CTLA-4 therapy. In some cases, mice developed durable immune protection that prevented tumor growth, suggesting long-term antitumor immune effects.
Further analyses revealed that ERK activation enhanced signaling within tumor cells and promoted infiltration of T-cells into tumors. Investigators also found evidence that MAPK/ERK signaling influences communication between tumor cells and microglia, the brain’s resident immune cells.
“What we realized is that when this pathway is activated, the tumor cells overall are more immunogenic,” Sonabend said. “They engage in a pathway called interferon response that is super important for T-cells to recognize the tumors. They’re more likely to drive T-cells into the tumor.”
The findings suggest MAPK/ERK activation could serve as a biomarker for identifying patients more likely to benefit from immunotherapy. According to Sonabend, the implications may extend well beyond checkpoint inhibitors alone.
“This biomarker might actually be relevant for all kinds of glioblastoma immunotherapy that rely on T-cells, which includes the vast majority of immunotherapy approaches,” he said.
At the same time, Sonabend cautions that MAPK activation is not a guarantee of response.
“It is very clear that this MAP kinase activation is necessary, but not sufficient,” Sonabend said. “Because you can have this pathway activated and not respond, but it is very clear that if you don’t have this pathway, you’re unlikely to respond.”
Looking ahead, the team hopes to translate the findings into clinical practice by refining how the MAPK pathway activity is measured and evaluated in patients. Sonabend said his team at Northwestern Memorial Hospital has already begun routinely testing tumor samples for the biomarker.
“We’re now routinely testing for this biomarker at Northwestern,” said Sonabend, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “One of the biggest challenges and interesting projects for me is to come up with a better way to look at MAP kinase activation that is easier and can be done by any lab in the world, so that it can impact brain tumor patients and not rely on a highly selected tertiary medical center.”
While additional studies and clinical validation will be needed, Sonabend said the new research provides some of the strongest evidence to date that MAPK/ERK signaling plays a role in shaping glioblastoma immunotherapy responses.
The study was supported by National Institutes of Health grants 1R01NS110703-01A1, 1U19CA264338-01, 1R01NS122395, 5R01CA290737, R37CA258426, P50CA221747 SPORE for Translational Approaches to Brain Cancer, and the Northwestern Nervous System Tumor Bank, as well as philanthropic support from the Sharon Moceri Foundation and Tina and Victor Kedaitis.
