Immunohistochemical staining analysis at baseline (above) and at relapse (below) in a patient with melanoma that developed acquired genetic resistance to anti–PD-1 ICB. Before treatment with immunotherapy, tumor cells (stained brown in panel S100) are invaded by T cells that produce interferon (IFN)-gamma (stained brown in panel CD8) and, in response, express proteins (MHC I, stained brown in panel MHC I) that allow them to be recognized by the immune system as well as other IFN-reactive proteins (PD-L1, stained brown in panel PD-L1). Image: Dr. Jesse Zaretsky
A drug that activates the body’s natural defenses by behaving like a virus may also make certain stealthy melanoma tumors visible to the immune system, allowing them to be better targeted by immunotherapy, a UCLA study has found. The findings open up the possibility of using drugs that mimic viruses to overcome immunotherapy resistance in certain tumors and help to create more personalized therapies for people with hard-to-treat cancers.
Interferons are proteins in cells that respond to viral infection by alerting the immune system to marshal its forces, including T cells, to combat viruses. When it comes to tumors, activating interferon signaling helps slow down tumor division and can lead to the release of molecules that recruit more immune cells to fight the tumor. That concept is the basis for adoptive T-cell therapy, a type of immunotherapy that involves extracting T cells from a patient and engineering them in the laboratory to recognize and kill cancer cells.
However, gene mutations that produced defective interferon signaling allowed some tumors to escape that immune system response. The defective signaling interrupts a critical pathway that normally would allow tumors to increase their antigen presentation — “an intricate machinery that makes tumors visible to T cells,” says Anusha Kalbasi, MD ’11, assistant professor of radiation oncology and member of UCLA’s Jonsson Comprehensive Cancer Center.
To overcome defective interferon signaling, the researchers turned to a virus-mimicking drug, called BO-112, that activates virus-sensing pathways in tumors. When the drug was injected directly into the tumor in the laboratory, the team discovered that the activation of virus-sensing pathways increased antigen presentation even when interferon signaling was defective. As a result, these tumors could be recognized and killed by T cells.
The study “gives us important insights into how tumors are recognized by the immune system,” says Antoni Ribas, MD (FEL ’98, ’01), PhD, director of the tumor immunology program at UCLA’s Jonsson Cancer Center. “New strategies to promote antigen presentation to make tumors more visible to the immune system will allow immunotherapy to be effective for even more tumor types.”
— Denise Heady
Uncoupling Interferon Signaling and Antigen Presentation to Overcome Immunotherapy Resistance Due to JAK1 Loss in Melanoma,” Science Translational Medicine, October 14, 2020
