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.
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