Restricting Interferon Signaling Can Reinforce Checkpoint Blockade

Checkpoint inhibitor drugs can take the brakes off the immune system’s response to cancer, but they often encounter resistance. It turns out that releasing one set of brakes often isn’t enough. Ways must be found to release multiple brakes, despite the growing risk of adverse side effects. An alternative approach, one recently explored by scientists based at the University of Pennsylvania, School of Medicine, amounts to adjusting the master cylinder, which controls the pressure in an auto’s brake system.

The Penn Medicine researchers assert that shutting down the interferon pathway may improve the response to checkpoint inhibitor drugs. The researchers point to the results of their preclinical study, which appeared December 1 in the journal Cell, in an article entitled “Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.”

According to this article, the interferon pathway is critical to a tumor’s resistance to immunotherapy. This resistance, however, can be overcome with a Janus kinase (JAK) inhibitor. The article’s authors even speculate that administration of a JAK inhibitor together with checkpoint monotherapy may bypass the need for combinations of checkpoint inhibitor drugs, which often come with serious side effects.

“The proposed approach has some elegance to it—rather than try to figure out all inhibitory pathways that the tumor has enabled, find a critical pathway that regulates many of the inhibitory signals and cripple that instead,” said the Cell paper’s senior author, Andy J. Minn, M.D., Ph.D., an assistant professor of radiation oncology in the Perelman School of Medicine at the University of Pennsylvania. “Interferon signaling is like a critical node in a network. Disable it and a large part of that network collapses.”

Today’s checkpoint inhibitor drugs target receptors such as programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which act as a type of “off switch” on a T cell to prevent it from attacking other cells. Inhibiting these pathways with one or a more of the drugs releases these “brakes” so the immune system can fight the disease. However, over half of patients on the drugs relapse or their cancer progresses.

Studies have shown that combining checkpoint inhibitors, ipilimumab and pembrolizumab, for instance, as well as adding radiation therapy, elicits promising tumor responses in patients. But many still do not respond because of additional unidentified “brakes.”

Using breast cancer and melanoma mouse models, the team led by Dr. Minn showed that prolonged interferon signaling in tumor cells increased resistance to checkpoint inhibitors through multiple inhibitory pathways, and that blocking this response resulted in improved survival and powerful tumor responses.

“We demonstrate that prolonged interferon signaling orchestrates PDL1 [programmed death ligand 1]-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4,” wrote the authors of the Cell paper. “Persistent type II interferon signaling allows tumors to acquire STAT1 [signal transducer and activator of transcription 1]-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors.”

Researchers modeled resistance to checkpoint therapy in breast cancer and melanoma mouse models with various lab techniques, including the genetic tool CRISPR, or clustered regularly interspaced short palindromic repeats, and found that treating the mice with checkpoint inhibitors (against PD1 and/or CTLA4) with or without radiation, along with the JAK inhibitor ruxolitinib, effectively restored complete responses and long-term survival in mice with tumors that are normally highly resistant to therapy.

“Both type I and II interferons maintain this resistance program,” the authors continued. “Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion.”

One checkpoint inhibitor (anti-CTLA4) and the JAK inhibitor in the breast cancer mouse model resulted in a 100% complete response and survival.

JAK inhibitors, U.S. Food and Drug Administration-approved drugs to treat myelofibrosis and psoriasis, target the well-studied interferon pathway, typically considered to be immunostimulatory. However, the authors found that over time interferon signaling changes how cells respond epigenetically to molecular signals in the tumor, switching from stimulatory to suppressive, similar to what happens in a chronic viral infection. Thus, blocking it switched off the tumor’s resistance in mice.

“To our surprise, blocking interferon-driven resistance not only antagonizes multiple inhibitory pathways that hinder combination therapies in mice,” Dr. Minn noted, “but it may also provide a general strategy to the challenge of designing complex combination checkpoint blockade therapies that seek to address the well-known problem of resistance.”

Downgrading the number of checkpoint inhibitors for therapy has its advantages, given the severe and sometimes life-threatening toxicities that come along with combination therapies, including autoimmune complications such as colitis and fatal myocarditis.

“There is a real translational implication here,” Dr. Minn insisted. “Because the interferon signaling pathway is targetable pharmacologically, we could perhaps mimic what we did in mice using JAK inhibitors that already exist for other purposes.”

The team is looking to begin a new clinical study in lung cancer patients based on their findings in the upcoming months. The researchers also identified two potential biomarkers, MX1 and IFIT1, which may help identify tumors in patients under the influence of this interferon suppression.