An 8-gene local immune signature for glioblastoma multiforme has been identified and could be used as a prognostic biomarker -- independent of the well-established biomarkers IDH1 and MGMT -- to identify patients at high or low risk of early death, researchers said.
Three of the genes (FOXO3, AIMP1, and ZTTB16) were protective against glioblastoma and five (CCL18, MMP9, FCGR2B, IL6, and IL10) increased risk of earlier death, Anhua Wu, MD, PhD, of The First Hospital of China Medical University in Shenyang, and colleagues reported online in Neurology.
Patients identified as high-risk lived an average of 348 days after diagnosis while patients considered low-risk lived an average of 493 days after diagnosis, the study showed. Median survival for glioblastoma -- the most common primary malignant brain tumor in adults -- is less than 2 years for patients with favorable prognostic factors.
"We've had luck with other types of cancer in removing the brakes on the immune system to allow it to fight the tumors, but this has not been the case with glioblastoma," said Wu. "If our discovery of these genes is validated in other studies, we could use this 'gene signature' to determine the best treatments or path of treatment."
Low-grade glioma did not have this signature, indicating that this immunologic biomarker is associated with the histologic grade of gliomas, the researchers said. "The signature was highly associated with the overall intensity of local immune response. The designated high-risk cases were demonstrated to exhibit an enhanced local immune phenotype compared to the low-risk ones."
The discovery of an immune signature for glioblastoma raises important questions about the role of the immune system in the pathogenesis of disease, Rifaat Bashir, MD, a retired neurologist in Reston, Va., and Nimish A. Mohile, MD, of the University of Rochester Medical Center in New York, said in an accompanying editorial.
However, they added, this study lacks clinical information that can affect prognosis, including age, baseline functional status, and extent of resection, meaning that clinical application remains uncertain.
On the other hand, they noted, these results point to a possible association between dysregulation of the immune environment and treatment resistance in glioblastoma, and to selecting patients on the basis of their responsiveness to immunotherapy or to checkpoint intervention.
"The looming question in neuro-oncology today is whether the advent of immunotherapy will help control an uncontrollable disease," the editorialists wrote. While this study doesn't provide an answer, it does bring us "one step closer to believing that one day we will be able to exploit the immune system to better treat glioblastoma," Bashir and Mohile said.
For the study, the researchers used microarray data from the Chinese Glioma Genome Atlas on 297 glioma samples (including 127 glioblastoma samples) to determine the local expression of known immune-related genes. Next, a local immune-related risk signature was developed to distinguish cases as being of high or low risk for an unfavorable prognosis. These findings were then externally validated using data from 536 glioblastoma samples from The Cancer Genome Atlas. A total of 322 genes were studied.
"High-risk patients conferred an enhanced intensity of local immune response compared to low-risk ones," the researchers said. "Additionally, the signature exhibited different distribution based on molecular features."
The study also showed the high-risk patients had shorter overall survival than low-risk patients, even after the high-risk patients received radiation and chemotherapy. "These results indicated that the immune risk signature-based classification could accurately identify patients with unfavorable prognosis irrespective of molecular and treatment characteristics," Wu and colleagues said.
Limitations of the study include its retrospective nature, and results "should be further validated by prospective studies," the researchers noted. "The capacity of our signature for predicting responses to immune-related therapy should be tested, along with its relationship with pseudo-progression."
The authors disclosed that they represent the Chinese Glioma Cooperative Group and that this work was supported by the National High Technology Research and Development Program of China, the National Natural Science Foundation of China, and the Science and Technology Department of Liaoning Province.
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