How IFN Signaling Could Inform Immunotherapy Options

The interferon (IFN) signaling pathway can tell the immune system to fight off cancer, but it can also be co-opted by cancer cells to put the brakes on the immune system. A new study, published today in Cell, shows how IFN signaling could help predict which patients are likely to respond to immunotherapies.

Interferons normally help activate the immune system to protect cells from viruses, and they get their name because they literally interfere with a virus’s ability to spread. However, IFNs can also impede the immune system.

“This paradoxical effect has been seen in other diseases—such as chronic viral infections—but our study shows how cancer cells take advantage of the suppressive properties of IFNs to interfere with cancer immunotherapy,” says senior author Andy J. Minn of the University of Pennsylvania.

The team previously found that IFNs have a role in cancer immunotherapy resistance. For the current study, researchers found that when IFNs put a brake on the immune system, cancer cells intercept and manipulate that signal. However, when IFNs are allowed to send signals to the immune system, immune cells are able to do their jobs and kill tumors. Understanding this balance of how IFN signals are routed to immune cells versus cancer cells could provide a biomarker for whether immunotherapy can be effective.

“If we know the signaling is tilted toward immune cells or toward cancer, we may be able to better predict if a patient is likely to respond,” Minn says.

For cases in which the IFNs’ signal is stronger in cancer cells, there could be a therapeutic answer. Blocking the signal in tumors would only leave the “go” signal, freeing up the immune system to attack the cancer. That’s exactly what happened when researchers tested the theory in pre-clinical models of melanoma, breast, and colorectal cancer treated with immunotherapies like PD-1 inhibitors or CAR T cells.

The next step is to figure out safe ways to make the IFNs’ “go” signal stronger or to block the “stop” signal.

“IFN signaling exists in the majority of human cancers, so this could end up applying more broadly,” Minn says.