Immunotherapy is an exciting and innovative cancer treatment that holds great hope for patients diagnosed with mesothelioma, the rare and deadly asbestos-related disease, but there is a wide range of responses to the protocol, with 25% of patients seeing dramatic improvement and others getting no benefit at all. In seeking a better understanding of this disparity, Italian researchers have discovered that DNA methylation patterns in mesothelioma tumors can predict which patients will respond well to checkpoint inhibitor drugs while sparing others a treatment that causes side effects without extending survival.
Mesothelioma DNA Methylation Study Identifies Four Distinct Tumor Subtypes
Published in the journal Nature Genetics, the study analyzed tumor samples from 91 mesothelioma patients who’d been treated with immune checkpoint inhibitors targeting CTLA-4 and PD-1. Drugs in this class have become standard treatment for non-epithelioid mesothelioma, but work for less than a quarter of patients, and the researchers wanted to know whether DNA methylation— a chemical modification that acts like an “off switch” for genes— plays a part.
The researchers discovered four distinct methylation patterns in mesothelioma tumors: demethylated, with few off switches; low; intermediate; and CIMP or CpG island methylator phenotype, where there are many off switches throughout the DNA. Further study showed that these patterns dramatically predicted survival and treatment response. Patients with LOW methylation tumors had a median overall survival that was three times longer than patients with CIMP (highly methylated) tumors. The three-year survival rate was 34% for LOW subtype mesothelioma patients, while all CIMP subtype patients had died within three years. Most importantly, responder patients who benefited from immunotherapy were predominantly in the LOW and demethylated groups, while non-responders were mainly in the intermediate/CIMP groups with heavy methylation.
Mesothelioma Tumor Methylation Patterns Shape Immune Response to Treatment
The researchers found that LOW-methylation tumors were packed with immune cells—particularly CD8+ T cells that kill cancer and CD20+ B cells that support immune responses. These tumors had activated an environment where checkpoint inhibitor drugs could work effectively by releasing the brakes on these immune cells. Conversely, CIMP mesothelioma tumors with heavy methylation had depleted immune microenvironments, with few cancer-fighting immune cells present. In these tumors, checkpoint inhibitors had nothing to activate. The methylation essentially switched off the genes involved in attracting and activating immune cells, making these tumors invisible or unwelcoming to the immune system.
Importantly, mesothelioma methylation patterns predicted immunotherapy response better than conventional biomarkers like PD-L1 expression or tumor mutational burden, which haven’t proven useful in mesothelioma. Methylation subtype was the only variable significantly associated with overall survival after correcting for other factors. The patterns didn’t predict chemotherapy response, which suggests that this is specifically about how tumors interact with the immune system.
Researchers Develop Online Tool for Mesothelioma Physicians
The mesothelioma researchers developed a publicly available online tool allowing doctors to classify patient tumors into methylation subtypes to help with treatment decisions. They also found that circulating tumor DNA in blood samples may reflect tumor methylation patterns, potentially providing an easier way to test patients without invasive biopsies. Rather than indicating that immunotherapy was not useful for patients with CIMP tumors, the scientists concluded that these patients could benefit from combining DNA methylation-reversing drugs with immunotherapy, an approach currently being investigated in clinical trials.
If you or someone you love has been diagnosed with mesothelioma, this type of research offers real hope for more effective treatment options in the future. For information on other resources available to you, visit Mesothelioma.net today, or call our Patient Advocates at 1-800-692-8608.
