New research from Sylvester Comprehensive Cancer Centerpart of the Miller Faculty of Medicine of the University of Miami (United States), It suggests a new path to improve the efficacy of immunotherapy in glioblastoma, one of the most difficult cancers to treat.
In depth
In his work published in ‘Journal of Clinical Investigation‘, researchers propose to suppress a protein called ZNF638 triggers an antiviral immune response, which makes immune control points inhibitors more effective. The discovery not only offers a possible new treatment strategy, but also Identify ZNF638 as a biomarker that could help customize immunotherapy for patients.
The glioblastoma It is the most common type of brain tumor in adults. Despite its prevalence, the evolution of glioblastoma patients has barely improved in the last 20 years. With a highly immunosuppressive microenvironment, clinical presentations Very variable between patients and physically demanding surgical conditions, glioblastoma is still exceptionally difficult to treat.
Inhibition of immune control points has been used successfully to treat more than a dozen diverse cancersbut because brain cancers are found in such a strong immunosuppressive environment, treatment has largely failed in individual attempts to date. “For many other cancers, immunotherapies have revolutionized the field, but in the case of brain tumors, we have not observed the same improvement,” he says Ashish H. Shahmain author of the study, neurosurgeon and researcher at Sylvester. “At least, not yet.”
Discovering what could make immune control points therapies more effective, or even ineffective, for glioblastoma patients is crucial to understand the best way to treat them. According to Shah’s new study, Viral mimicry could be the answer. Specifically, viral mimicry is an avant -garde tool in cancer treatmentwhich can be the key path to achieve that the inhibition of immune control points is effective in the treatment of glioblastoma.
More details
The objective of viral mimicry is to deceive the body to think that the tumor has a viral infectionwhich triggers an immune response. For millions of years, the human genome has compiled virus fragments called human endogenous retrovirus. Generally, our body silence these retroviral genes through various mechanisms, in particular the Hush protein complex. In viral mimicry, lDoctors induce the patient’s body to “disable” these inactive viral fragments. These ancient fragments are not strong enough to cause a real viral infection, but still trigger an antiviral immune response. This antiviral response can make tumors more susceptible to immunotherapies.
“We are using evolution to attack tumors“Shah highlights. Viral mimicry was used successfully for the first time to increase the susceptibility of ovarian cancer to ICI in 2015. Since then, it has been used in at least four other types of cancer, and it is a rapidly developing research area. However, He had not successfully applied to brain tumors to Shah’s new job.
The question for Shah and his team, so it was how they could use viral mimicry so that immune control points inhibitors work in glioblastoma. To do this, they resorted to ZNF638, a key regulator of the protein group that silences retrovirus. By suppressing znf638 in the tumor, They could generate a viral mimicry response, thus opening the door for immune control points to finally treat glioblastoma.
Researchers first searched for cancer databases, documenting associations between ZNF638 and immune factors, such as immune cell infiltration. They analyzed the genetic data of glioblastoma patients and discovered that patients with the greatest response to therapy with immune control points naturally had a lower expression of ZNF638 and higher survival rates. Cellular experiments and unicellular RNA sequencing revealed that tumors with low levels of ZNF638 tended to present a greater infiltration of immune cells, and the retrovirus monitoring system was active. This connection between ZNF638 and antivirals was also observed in published data of patients. It was possible that the targeting of ZNF638 could create conditions of “viral mimicism” in tumors.
To take into account
With these results, the researchers evaluated the impact of the suppression of ZNF638 on preclinical trials, directing it only to tumor cells and leaving the healthy brain tissue intact. The combination of the suppression of ZNF638 with therapy with inhibitors of immune control points improved the efficacy of the treatment: The suppression of ZNF638 reduced tumor growth, increased the infiltration of T lymphocytes and improved survival.
“The most amazing findings were found in the clinical data, where patients with low expression of ZNF638 showed better responses to immunotherapy,” says Jay Chandar, a fourth -year medical student in the SHAH laboratory and co -author of the study. “This firmly supported our idea that the suppression of ZNF638 would make tumors more susceptible to immunotherapy“
The promising results point to the potential of ZNF638 as a biomarker, which will allow defining personalized treatment plans. Immune control points inhibitors are not currently approved for the treatment of glioblastoma, so previous patients have been evaluated case by case, SHAH affects. The use of ZNF638 as biomarker could help change this situation by predicting which patients would probably respond to ICI therapy.
While a new biomarker is the most immediate result, the long -term objective remains to develop a drug that penetrates the brain to Attack ZNF638 in glioblastoma, which would allow ICI to effectively use to treat more patients.
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