Suppressing Key Protein May Unlock Immunotherapy for Glioblastoma

ZNF638 inhibition triggers “viral mimicry,” making tumors more susceptible to treatment.

Glioblastoma has remained one of the toughest cancers to treat, resisting even the latest advances in immunotherapy.

But new research from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, suggests a way forward: suppressing a protein called ZNF638 triggers an antiviral immune response, making immune checkpoint inhibitors more effective.

The discovery not only offers a potential new treatment strategy but also identifies ZNF638 as a biomarker that could help personalize immunotherapy for patients. The findings appear in the March 17 issue of the Journal of Clinical Investigation.

Glioblastoma is the most common type of brain tumor in adults, with about 12,000 cases in the United States each year. Despite the disease’s prevalence, outcomes for patients with glioblastoma have barely improved in the last 20 years. With a strongly immunosuppressive microenvironment, highly variable presentations between patients, and physically challenging surgical conditions, glioblastoma remains exceptionally difficult to treat.

“Brain tumors are one of the most formidable foes in medicine. Our current treatment options are simply insufficient.” said Ashish H. Shah, M.D., senior author of the study, and a neurosurgeon and researcher at Sylvester.

Immune checkpoint inhibition has been successfully used to treat more than a dozen diverse cancers, but because brain cancers are in such a strongly immune-suppressive environment, the treatment has largely failed in the case-by-case attempts to date.

“For many other cancers, immunotherapies have completely changed the field, but for brain tumors, we haven’t seen that same improvement. At least, not yet.” Shah said.

Learning what could make immune checkpoint therapies more effective – or effective at all – for glioblastoma patients is critical for understanding how to treat patients best. According to Shah’s new study, viral mimicry may be the answer.

Viral Mimicry

Viral mimicry, a tool at the leading edge of cancer treatment, maybe the key path forward in making immune checkpoint inhibition effective for treating glioblastoma.

The goal of viral mimicry is to trick the body into thinking the tumor has a viral infection, prompting an immune response. Over millions of years, the human genome has collected fragments of viruses called human endogenous retroviruses. Most of the time, our body silences these retroviral genes through various mechanisms, particularly the HUSH protein complex.

In viral mimicry, clinicians trigger the patient’s body to “un-silence” these inactive viral fragments. These ancient fragments are not strong enough to cause a real viral infection, but they still trigger an anti-viral immune response. That antiviral response can make tumors more susceptible to immunotherapies.

“We’re using evolution to attack tumors,” Shah said. Viral mimicry was first successfully used to make ovarian cancer more susceptible to ICI in 2015. It has since been used in at least four other cancers, and it’s a rapidly developing area of research. But it had not been successfully applied to brain tumors until Shah’s new work.

Un-silencing Ancient Viruses

The question for Shah and his team, then, was how they could use viral mimicry to make immune checkpoint inhibitors work for glioblastoma. For that, they turned to ZNF638, a key regulator of the group of proteins that keep retroviruses silent. By suppressing ZNF638 in the tumor, they might create a viral mimicry response, opening the doors to immune checkpoint inhibitors effectively treating glioblastoma at last.

The researchers first searched cancer databases, documenting associations between ZNF638 and immune-related factors such as immune cell infiltration. They analyzed glioblastoma patients’ genetic data and found that patients who were more responsive to immune checkpoint inhibitor therapy naturally had lower expressions of ZNF638 and higher survival rates.

Cell-based experiments and single-cell RNA sequencing revealed that tumors with low ZNF638 tended to have more immune cell infiltration, and the monitoring system for retroviruses was active. This ZNF638-antiviral connection was seen in published patient data, too. It was possible that targeting ZNF638 could create “viral mimicry” conditions in tumors.

Armed with these results, the researchers tested the impacts of suppressing ZNF638 in preclinical tests, targeting it only in the tumor cells and leaving healthy brain tissue untouched. Combining ZNF638 targeting with immune checkpoint inhibitor therapy improved the treatment’s efficacy: ZNF638 suppression had decreased tumor growth, increased T-cell lymphocyte infiltration and improved survival times.

“The most surprising findings were in the clinical data, where patients with low ZNF638 expression had improved responses to immunotherapy. That strongly supported our whole idea that knocking down ZNF638 would make tumors more susceptible to immunotherapy.” said Jay Chandar, a fourth-year medical student in Shah’s lab and study co-author.

“With previous trials using ICI to treat glioblastoma having largely failed, it’s exciting to find a novel therapeutic target and see that viral mimicry could help. I’m optimistic this could improve prognoses for glioblastoma patients.” said Deepa Seetharam, Ph.D., a postdoctoral scholar in the Department of Neurosurgery and study co-author.

The Future of Immunotherapy for Glioblastoma

The promising results point to the potential for ZNF638 to be a biomarker, shaping personalized treatment plans. Immune checkpoint inhibitors are not currently approved for treating glioblastoma, so previous patients have been on a case-by-case basis, Shah said.

Using ZNF638 as a biomarker could help change that by predicting which patients would likely be responsive to ICI therapy.

While a novel biomarker is the most immediate outcome, the long-term goal remains developing a brain-penetrating drug to target ZNF638 in glioblastoma, allowing ICI to be used effectively to treat more patients.

“Then we’ll really be changing the game. A synergistic treatment like that is the future of immunotherapy in treating glioblastoma.” Shah said.

“Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models”

Authors: Deepa Seetharam, Jay Chandar, Christian Ramsoomair, Jelisah Desgraves, Alexandra Alvarado Medina, Michele Ceccarelli, Katherine Chiappinelli, Maria Figueroa, Defne Bayik, and Ashish Shah et al.

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