Immune Signature May Aid Prognosis, Therapy in Glioblastoma

Pauline Anderson

May 26, 2016

Amid growing interest in the role of the immune system in glioblastoma multiforme (GBM), researchers in China have developed a method to identify patients with a worse prognosis, based on immune profiles.

Not only might this unique immune "signature" help identify patients with a worse outcome, but may also help determine immunotherapy approaches.

"Our study results suggest that editing the local immune status could be a promising treatment for glioma and strengthens our belief that proper use of immune therapy could improve clinical outcome and maybe cure glioma," study author Anhua Wu, MD, PhD, Department of Neurosurgery, The First Hospital of China Medical University, told Medscape Medical News.

The study, led by Wen Cheng, MD, PhD, Department of Neurosurgery, The First Hospital of China Medical University, Beijing, was published online May 25 in Neurology.

GBM, a tumor of the glial cells, is the most common and aggressive form or brain cancer in adults. Life expectancy is less than 2 years, even after treatment with surgery, radiation, and chemotherapy.

The character of glioma is determined by the expression pattern of numerous genes, Dr Wu said.

From the Chinese Glioma Genotype Atlas, Dr Wu, Dr Cheng, and colleagues obtained whole genome expression information of 297 patients with glioma using messenger RNA microarray.

On the basis of the expression data, they profiled the immune-related phenotype according to histologic grade and classification. A histologic diagnosis defined 170 of the tumors as lower-grade glioma (grades II and III) and 127 as GBM.

Of the 322 immune-related genes they studied, 8 showed an association of the gene expression with prognosis in patients with GBM. Three genes were protective, while the other 5 were associated with poor outcome.

High/Low Risk

Researchers divided patients with glioblastoma into high or low risk based on the eight-gene–based risk signature. They found that those with high risk were twice as likely to have a shorter survival time after their diagnosis as those with low risk based on the signature.

Overall survival in the high-risk group was 348 days vs 493 days for the low-risk group (hazard ratio, 2.16; 95% confidence interval [CI], 1.58 - 3.48; P < .0001).

Progression-free survival was also "notably reduced" in the high-risk patients, the researchers note, with a median progression-free survival of 242 days vs 369 days for the low-risk group (hazard ratio, 1.89; 95% CI, 1.36 - 2.95; P = .0005).

The results were the same after researchers adjusted for other factors that could affect survival, including the type of treatment received.

The findings were externally validated with data from 536 GBM samples from The Cancer Genome Atlas.

The new research has several implications. The immune signature allows patients to be stratified into high- or low-risk groups "for accurate prognosis predicting," said Dr Wu.

And it may allow researchers to obtain information on the local immune environment that will guide therapy and the development of novel treatments, he said.

The key question in glioma research, according to Dr Wu, has been whether the launch of immunotherapy will help control GBM, which is such an "uncontrollable disease." The new findings suggest that targeted immunotherapy may indeed be a way to boost the "fighting ability" of the immune system, he said.

"Our study indicates a possible treatment strategy by shaping the immune microenvironment, and the eight critical genes could be regarded as alternative targets either alone or, maybe even better, in combination."

Not Without Limitations

According to accompanying editorial, "bioinformatics modeling" and statistical methods help investigators answer complex biological and genetics questions generated by a large body of data.

However, using advanced statistical models to define an immunologically related gene expression pattern or "signature" for GBM "is not without limitations," Rifaat Bashir, MD, Reston, Virginia, and Nimish A. Mohile, MD, Department of Neurology, University of Rochester Medical Center, New York, write in their editorial.

"This study, like many other large database studies, lacks meaningful clinical information that we know affects prognosis," they note. "This information includes age, baseline functional status, and extent of resection. Whether the results of this study can be effectively translated into clinical use is unknown."

The finding of an immune signature raises important questions not only for prognosis but also for understanding the role of the immune system in the pathogenesis of GBM, note Dr Bashir and Dr Mohile.

"These results provide credibility to the idea that aggressiveness and maybe even the resistant nature of GBM are associated with dysregulation of its immune environment. This approach may also help in selecting pathways as well as patients who are susceptible to treatment with immunologic manipulation or checkpoint intervention."

The "looming question" in neuro-oncology is whether the advent of immunotherapy will help control an uncontrollable disease, they write. "The work by Cheng et al. does not answer this question but it brings us one step closer to believing that one day we will be able to exploit the immune system to better treat GBM."

The study was supported by the Chinese National High Technology Research and Development Program, the Chinese National Natural Science Foundation, and the Liaoning Province Science and Technology Department. The study authors and the editorialists have disclosed no relevant financial relationships.

Neurology. Published online May 25, 2016. Abstract  Editorial

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