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New Influenza Findings Could Have Key Impact on Cancer Therapies

March 19, 2020

Balachandran expects that synthetic Z-RNAs and other ZBPI agonists, by mimicking an influenza infection and activating ZBP1 in resistant tumors, will alert the immune system to the malignancy and promote positive immunotherapeutic outcomes in otherwise refractory disease.Balachandran expects that synthetic Z-RNAs and other ZBPI agonists, by mimicking an influenza infection and activating ZBP1 in resistant tumors, will alert the immune system to the malignancy and promote positive immunotherapeutic outcomes in otherwise refractory disease.

PHILADELPHIA (March 19, 2020) – In new findings published in the prestigious journal Cell, researchers at the Fox Chase Cancer Center have clarified a fundamental host defense mechanism that detects the presence of influenza virus and rapidly destroys infected cells.

The findings are a “major milestone” that has exciting implications for a variety of fields, including cancer immunotherapy, said Siddharth Balachandran, PhD, lead author of the study and professor in the Blood Cell Development and Function program at Fox Chase.

In previous research, Balachandran and other researchers had identified a protein called ZBP1 that is essential for sensing the presence of influenza virus in lung cells. But they did not know how ZBP1 was being activated. “In other words, what was ZBP1 ‘seeing’ that told it the cell was infected? Now, we know the answer,” Balachandran said.

It turns out that ZBP1 sees Z-RNA, a new form of RNA produced by influenza virus.

“Z-RNA is made by the flu virus as it replicates in lung cells. ZBP1 senses these foreign Z-RNAs and interprets them as a sign that the cell is infected. It then pushes an autodestruct button that not only kills the infected cell, but also alerts the immune system to the presence of the virus,” Balachandran said.

“Folks have been looking for Z-RNA for decades. This particular structure of RNA is what is called a pathogen-associated molecular pattern, and discovering a new such pattern is a major milestone. It also has significant implications for cancer immunotherapies,” he added.

“Although immunotherapy is clearly the most promising new cancer treatment approach in decades, a major problem with current immunotherapeutic drugs is that over half of all patients either are refractory to treatment or will develop resistance to the therapy. Making such resistant cancers sensitive to treatment is therefore a huge unmet need,” Balachandran said.

“Mimicking a virus infection in resistant tumors has the potential to fill this need, because it can rekindle the immune response to the tumor. The tumor cells now light up as ‘infected,’ and in doing so, become visible to current immunotherapeutic modalities such as the checkpoint inhibitor nivolumab.”  

Balachandran expects that synthetic Z-RNAs and other ZBPI agonists, by mimicking an influenza infection and activating ZBP1 in resistant tumors, will alert the immune system to the malignancy and promote positive immunotherapeutic outcomes in otherwise refractory disease.

The research was a collaboration between the Balachandran laboratory and laboratories at the University of Texas, St. Jude Children’s Hospital, the University of Pennsylvania, and the University of Miyazaki in Japan.

The paper, “Influenza virus Z-RNAs induce ZBP1-mediated necroptosis,” was published in Cell.

      

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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