The inside of a solid tumor has an environment distinct from the tissues around it. Rapid cell growth and proliferation outpaces blood-vessel development, leaving cells deep inside deprived of adequate oxygen and nutrients like glucose and amino acids.

In part because of these conditions, solid tumors are inhospitable to immune cells, a fact that has frustrated attempts to treat them with immunotherapies.

Now, researchers at Penn led by Serge Fuchs, a professor of cell biology in the School of Veterinary Medicine and director of Penn Vet’s Mari Lowe Center for Comparative Oncology, have discovered how solid tumors evade immune detection. Using this new understanding, they have shown how immunotherapies can be modified to kill even these stubborn cancers.

The work focused on a protein called type I interferon receptor (IFNAR1), which is activated by interferon. Occurring naturally in the body, interferon is also given as a therapy for cancer, infections, autoimmune diseases, and other conditions.

Earlier work by Fuchs and colleagues showed that IFNAR1 levels go down in response to the deficit of oxygen and nutrients that is present deep inside solid tumors. In the new study, published in Cancer Cell, the researchers examined tissue samples from colorectal cancer patients and found that IFNAR1 protein levels were low in the cancerous tissue compared to the healthy tissue. Lower IFNAR1 levels were also associated with poorer outcomes in these patients.

“If we can reverse that, then we’ll probably improve the outcome of treatment,” Fuchs says.

Turning to mice, the team found that animals with colorectal cancer had a corresponding decline in IFNAR1 protein, but those bred to have a form of IFNAR1 resistant to degradation had fewer tumors than normal mice.

The researchers determined a reduction in IFNAR1 greatly compromised the ability of T cells to survive inside tumors, thus limiting their ability to fight and kill the cancer.

Using this knowledge to make a more-effective immunotherapy, the researchers stabilized IFNAR1 on “killer” T cells by inhibiting enzymes that normally degrade the receptor. They then delivered these T cells to mice with colorectal cancer. The cells were able to effectively survive within tumors and suppress their growth.

Fuchs and colleagues are hopeful that they will be able to use a similar approach in treating humans with CAR-T cell therapy, an approach that Carl June and others at Penn’s Perelman School of Medicine have used to great effect in blood cancers.

“Technically, it’s not very simple, but it should be feasible,” Fuchs says. “And that would be very, very sweet.”