Solid tumors present a stressful environment. They grow so rapidly
that blood-vessel growth can't keep up, thus cells deep inside tumors
are often left wanting for oxygen or nutrients like glucose and amino
Immunotherapies have revolutionized cancer treatment, offering hope
to those whose malignancies have stubbornly survived other existing
treatments. Yet solid tumor cancers are often resistant to these
‘Downregulation of the the protein type I interferon receptor IFNAR1 is required for the generation of immune-privileged niches in the tumor microenvironment.’
New findings from a University of Pennsylvania-led team untangle one
of the ways tumors evade immune detection and show how immunotherapies
can be modified to tackle even these solid tumors.
The focus of the study was the protein type I interferon receptor
IFNAR1, which is activated by interferon, a molecule that is known to
fight cancers and is itself a treatment for cancer, infections and other
conditions. When a tumor forms, the hypoxic environment of its
fast-growing mass leads to a reduction in levels of the interferon
receptor on T cells. This reduction precipitates the T cells' demise,
thus creating an environment where cancer cells can survive and
"We found that this downregulation of the receptor is required for
the generation of immune-privileged niches in the tumor
microenvironment," said Serge Y. Fuchs, a professor of cell biology in
Penn's School of Veterinary Medicine, director of the school's Mari Lowe
Center for Comparative Oncology and senior author on the study.
"Accordingly, this decreases the efficacy of immune therapies. So, if we
can reverse that, then we'll probably improve the outcome of
Fuchs collaborated on the work with Penn Vet's Kanstantsin V.
Katlinski, Jun Gui, Yuliya V. Katlinskaya, Angelica Ortiz, Riddhita
Chakraborty, Sabyasachi Bhattacharya, Christopher J. Carbone, Daniel P.
Beiting and Ellen Puré; Priya Chatterji, Anil K. Rustgi and Constantinos
Koumenis of Penn's Perelman School of Medicine; the Medical College of
Wisconsin's Melanie A. Girondo, Amy R. Peck and Hallgeir Rui; and the
Medical University of South Carolina's J. Alan Diehl.
The work appears in the journal Cancer Cell
Fuchs' laboratory has long been intrigued by IFNAR1, a receptor that
plays an important role in cancers, inflammation, autoimmune diseases
and viral infections. Most cellular receptors are subject to a negative
feedback loop; when their corresponding extracellular molecule activate
the receptor, it triggers a pathway that then leads to that receptor
being reduced, presumably to avoid the cell being overloaded with
signaling through that pathway.
Yet about a decade ago, Fuchs and colleagues discovered that IFNAR1
is downregulated not only upon activation with interferon but also
through another pathway that robs the cells of their ability to
"And when we found that some of the stimuli that can remove IFNAR1
from the cell surface are similar to those that occur in the tumor
microenvironment," Fuchs said, "we became curious if the loss of the
receptor happens in the tumors."
At the same time, researchers including study author Koumenis had
found that immune-related genes dropped in expression in the deep tumor
microenvironment, creating what is referred to as an immune-privileged
In the current work, the research team investigated whether IFNAR1
was involved in this dip in immunity, looking specifically at colorectal
cancer, a disease that does not respond well to immunotherapies.
Examining tissue samples from people with colorectal cancer, the
researchers found dramatic differences in IFNAR1 protein levels between
normal and cancerous tissue; the cancer cells showed complete or
near-complete loss of the protein. This loss was also associated with
poorer outcomes in patients.
The researchers then turned to mice to determine exactly how IFNAR1
loss related to tumor growth. Mice with a form of colorectal cancer had a
corresponding decline in IFNAR1 protein, but those bred to have a form
of IFNAR1 resistant to degradation had fewer tumors.
The researchers next used a model in which mice received a
transplant of tumor cells. While tumors grew on genetically normal mice,
mice with the degradation-resistant IFNAR1 either rejected the tumor
cells or displayed a delay in tumor growth.
Because T cells are known to be able to fight tumors, the
researchers looked at T cell levels in mice with the
degradation-resistant form of IFNAR1 compared to the normal mice and
found that the latter group had significantly reduced numbers of a
number of immune cells, including so-called "killer" T cells, inside the
tumors. Further experiments confirmed that the downregulation of IFNAR1
on T cells greatly decreased the cells' ability to survive in the tumor
This discovery helps explain why immunotherapies based on
genetically engineering T cells have low efficacy in solid tumor
cancers: they simply can't survive long enough to have an effect against
the cancer cells.
To put their findings into action, the researchers tweaked the
typical T cell immunotherapy approach by stabilizing IFNAR1 in the
transferred T cells by inactivating or inhibiting the enzymes normally
involved in degrading the receptor. This was able to restore levels of
the receptor in the cytotoxic T lymphocytes, increasing their numbers
inside the tumors, where they had a strong anti-tumorigenic effect.
"Based on that we were able to make a better immunotherapy," said Fuchs.
He and colleagues are working to develop a model where they could
use a drug to stabilize the receptors and are also investigating a way
to put a stabilized receptor into a CAR-T cell therapy.
"Technically it's not very simple, but it should be feasible," Fuchs said. "And that would be very, very sweet."