Targeting protein linked to eczema and asthma promotes ovarian cancer survival

Researchers at the Icahn School of Medicine at Mount Sinai Hospital have discovered the way ovarian cancer tumors manage their environment to resist immunotherapy and identified a drug target that can overcome this resistance.

In the study, which was published in the journal Cell, researchers found that ovarian cancer cells produce a molecule called interleukin-4 (IL-4), which is commonly associated with asthma and eczema. Cancer cells use IL-4 to create a protective environment that closes off access to immune killer cells, making tumors resistant to immunotherapy.

Ovarian cancer is one of the most lethal cancers; 50% of patients die within five years of diagnosis. Unfortunately, immunotherapy drugs targeting the PD-1 molecule, which have demonstrated efficacy in the treatment of melanoma and lung cancer, have failed to significantly improve survival rates in ovarian cancer.

This is partly because ovarian tumors contain fewer mutations, so it is more difficult for the immune system to recognize them. It is now clear that these tumors can resist immunotherapy by creating barriers that prevent immune cells from entering the area where they live. The crucial question, the researchers said, was how do tumors create this protective environment?

To answer this question, a research team led by Alessia Baccarini, PhD, associate professor of immunology and immunotherapy, and Brian D. Brown, PhD, director of the Icahn Institute for Genomics at Mount Sinai Hospital, used a new genomic technology known as Perturb-map.

It elucidates the role of each gene in controlling the tumor environment.

The experiments showed that deleting the IL-4 gene from ovarian cancer cells made the tumors susceptible to PD-1 antibody therapy.

The researchers then tested a combination of drugs blocking PD-1 and IL-4 receptors on mice with aggressive metastatic ovarian cancer and found that this combination treatment significantly increased survival rates.

Additional preclinical studies have shown that ovarian cancer uses IL-4 to reprogram macrophages (a type of immune cell), into defenders of cancer cells. IL-4 reprogrammed macrophages prevented T cells from destroying cancer cells.

However, blocking IL-4 changed the local environment surrounding the cancer cells, making the malignant cells vulnerable to destruction by the immune system.

“Ovarian cancer is recognized as almost unresponsive to existing immunotherapies, so it was surprising to us that by blocking just one molecule, IL-4, and changing the tumor microenvironment, we could make these hard-to-treat tumors treatable,” says Dr. Brown. “This is further proof that it can be effective to target not only the cancer cells, but also the tumor environment.”

While these results are encouraging, researchers emphasize that clinical trials are needed to determine whether IL-4 targeting therapy can improve patient outcomes.

The IL-4 pathway is already being used to treat conditions such as eczema, and researchers believe that by targeting this pathway in ovarian cancer, it may be possible to help women facing this horrible disease.

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Published: 08.11.2024

Updated: 08.11.2024

Medical author, Medical editor:

Stepan Yuk

Medical expert:

PhD. Olexandr Voznyak