Gürkan Mollaoğlu, Ph.D., assistant professor in the Department of Microbiology, was recently published in Cell for his study “Ovarian cancer-derived IL-4 promotes immunotherapy resistance,” which could open new doors for treating ovarian cancer patients who are resistant to immunotherapy.
Ovarian cancer remains one of the most challenging cancers to treat, affecting tens of thousands of women each year. With a lifetime risk of 1 in 87, it’s known as a “silent killer” because it often shows no early symptoms, leading to late-stage diagnoses and grim survival rates—only about half of those diagnosed survive beyond five years. However, a recent breakthrough may offer new hope.
The researchers discovered that ovarian tumors use interleukin-4 (IL-4) molecules to evade immune system attacks. While current treatments such as surgery and chemotherapy can initially shrink tumors, many patients experience recurrence with drug-resistant tumors. Immunotherapy has shown promise in other cancers, but for ovarian cancer, it has largely failed.
The team of scientists employed a powerful CRISPR tool, developed by Dr. Mollaoğlu’s postdoctoral mentor’s lab at the Icahn School of Medicine at Mount Sinai in New York, and tested multiple factors produced by ovarian tumors, discovering that IL-4 plays a crucial role in forming a "tumor microenvironment" that shields cancer cells.
“Ovarian tumors are made up of diverse cell types, each using different factors to manipulate the surrounding cells and evade treatment,” Mollaoğlu said. “This environment impacts how a tumor responds to therapy, making it critical to identify these factors for potential therapies.”
The team’s findings were striking. When IL-4 was inhibited, ovarian tumors became more susceptible to PD-1 inhibitors, a class of immunotherapy drugs that includes Pembrolizumab (Keytruda) and Nivolumab (Opdivo). By combining an IL-4 receptor inhibitor with PD-1 immunotherapy, they found a way to overcome ovarian cancer's resistance to immunotherapy. The study suggests that Dupilumab (Dupixent), an IL-4 receptor inhibitor currently used to treat eczema and asthma, could be used in combination with PD-1 inhibitors to treat ovarian cancer.
The study further revealed that IL-4 affects macrophages, a type of immune cell found in high quantities within ovarian tumors. Single-cell analysis showed that macrophages change their behavior in response to IL-4, triggering a chain reaction in the tumor microenvironment that leads to immunotherapy resistance. Single-cell and pathological analyses of human ovarian tumors suggested that the same mechanism may be responsible for immunotherapy resistance in ovarian cancer patients.
“These findings are incredibly promising,” Mollaoğlu said. “While we still need clinical trials to confirm the efficacy of combining IL-4 and PD-1 inhibitors, our results in preclinical models give us hope for improving treatment outcomes for ovarian cancer patients.”
For more information on the study and full author details, please see the article in Cell.