Researchers at Memorial Sloan Kettering Cancer Center (MSK) have uncovered a previously unknown reason why mesothelioma tumors become resistant to immunotherapy. At the same time, they’ve identified several promising strategies to reverse that resistance. Their discovery could significantly improve treatment outcomes for patients with the rare and aggressive asbestos-related cancer.
Mesothelioma Tumors Use Missing Gene to Hide from Immune System
Mesothelioma is notoriously difficult to treat, but immunotherapy treatments that use the body’s own immune system to fight the rare form of cancer have shown great promise. Still, even patients who initially respond well to the innovative treatment often see their tumors stop responding over time. Understanding why this happens has been one of the biggest challenges for mesothelioma researchers.
The MSK team discovered that a missing or damaged gene called NF2, which acts as a sort of security guard inside mesothelioma’s cells, is a key culprit. When NF2 works properly, it helps keep the immune system informed about what’s happening inside the tumor, but when NF2 is lost or damaged, the tumor reverses its actions, blocking immune cells from doing their job. The researchers found that mesothelioma tumors that had become resistant to CAR-T cell therapy, which uses a patient’s own immune to attack cancer, consistently showed lower levels of NF2 than tumors that were still responding to treatment.
Making matters worse, the mesothelioma tumors with NF2 loss were doing more than blocking the immune system: they were actively recruiting the wrong kind of immune cells. Instead of attracting cancer-fighting immune cells, they drew in a specific type of immune cell called a macrophage that normally helps fight infection. The macrophages actually protect the tumor, blocking cancer-fighting T cells from getting through.
Mesothelioma Cell Resistance Can Be Reversed by Targeting Multiple Pathways
The researchers found that blocking the chemical signals that mesothelioma tumors use to recruit these protective macrophages restored the tumor’s sensitivity to CAR T cell therapy. Blocking retinoic acid, a chemical that helps tumors attract these protective macrophages, also reversed resistance. These findings suggest that testing patients for NF2 loss before starting immunotherapy could help doctors identify who is most likely to develop resistance—and who might benefit from combination treatments targeting the Hippo pathway or macrophage-recruiting signals alongside standard immunotherapy.
If you or someone you love has been diagnosed with mesothelioma, discoveries like this promise new options for more effective personalized therapy. For more information on resources available to you, contact the Patient Advocates at Mesothelioma.net today at 1-800-692-8608.
