A protein already targeted by FDA-approved cancer drugs may also help the body fight influenza, according to new research from The Jackson Laboratory (JAX).
Published in Cell Reports , the study found that Programmed Death-Ligand 1 (PD-L1), a protein best known for helping tumors evade immune attack, instead helped immunocompromised mice clear flu-infected lung cells and survive infection.
The findings challenge long-standing assumptions about PD-L1's role in the immune system. While cancer therapies work by blocking PD-L1 to boost immune attack on tumors, the new research suggests that enhancing PD-L1 signaling may help the body control severe respiratory viral infections, especially in people with T cell immunodeficiencies such as those with HIV or immunosuppression after chemotherapy.
"This discovery suggests that a pathway targeted in cancer could also be useful in infectious disease, but in the opposite way. Cancer therapies block PD-L1, whereas in flu, enhancing it may strengthen host defense," said Silke Paust, a JAX professor and immunologist who directed the research.
PD-L1 is a protein that sits on the surface of tumor cells and has traditionally worked with PD-1, a protein on immune cells, to suppress immune activity. For years, scientists assumed that was PD-L1's only role: to help tumors hide from the immune system by switching off immune cells that would otherwise attack them. But after unexpectedly finding PD-L1 on human and mouse lung immune cells, Paust's team began investigating whether it might do more than protect tumor cells from immune attack.
"Cancer drugs block the interaction of PD-L1 with PD-1 to enhance immune killing of tumors," Paust said. "In influenza, however, PD-L1 instead promotes immune killing of infected cells and helps protect the host, independent of PD-1."
The researchers used mice lacking T and B cells and therefore dependent on innate immunity from natural killer (NK) cells, which rapidly kill infected or abnormal cells without prior exposure. NK cells are an important antiviral defense and may be especially relevant in people with T cell deficiency.
"Most healthy people don't die from the flu when they get sick," Paust said. "It's really the very young, the very old, and certainly the immunocompromised who are at risk of dying. Immunocompromised patients with flu usually die from severe complications, especially viral or secondary bacterial pneumonia leading to respiratory failure, sometimes with sepsis and multi-organ failure."
After flu infection, NK cells in the lungs produced high levels of PD-L1. When Paust and her team treated mice with an antibody that activates PD-L1, the animals lived longer because the NK cells were better able to destroy cells infected with virus. Importantly, this improved survival did not increase lung damage, suggesting better viral control without harmful inflammation.
PD-L1 signaling in NK cells also increased expression of a molecule used to destroy virus-infected cells called tumor necrosis factor-related apoptosis-inducing ligand, or TRAIL. Analysis of human lung tissue and blood samples from COVID-19 patients showed similarly increased expression of PD-L1 and TRAIL in lung NK cells, suggesting the newly identified mechanism may extend beyond mice.
Next, the researchers will study how PD-L1 behaves in healthy lungs with a full immune system, including T and B cells, which also carry PD-1.
"We still don't understand how PD-L1 behaves in healthy lungs with a full immune system," Paust said. "Figuring that out could help us understand how the lung regulates immune responses to viral infection."
If confirmed in additional studies, the findings could inform next-generation cancer immunotherapies, since similar PD-L1 signaling mechanisms may also operate in tumors. The work could also help explain why therapies targeting PD-L1 and PD-1, two sides of the same immune checkpoint pathway, do not always produce identical effects in cancer patients.
"If PD-L1 is sending signals inside cells during flu infection, it may do the same in cancer and other diseases," Paust said. "That could reshape how we think about immune checkpoints, because this molecule's role may depend on which cells carry it. In the lung, PD-L1 may be doing two jobs at once."
This work was supported by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (R01 AI174590) and unrestricted funds from the Scripps Research Institute.
Other authors are Kayla Frank of The Scripps Research Institute; Himani Sharma, Efthymios Motakis, and Nooshin Nourbakhsh of The Jackson Laboratory; Shawn Abeynaike and Tridu R. Huynh of The Scripps Research Institute; and Cheryl A. Jones, Scott K. Johnson, and S. Mark Tompkins of University of Georgia.
