Why Immunotherapy Works for Some, But Not All, Mesothelioma Patients
New research points to DNA methylation as a key factor in predicting who may respond to treatment and a potential new way to target resistant tumors.
Immunotherapy has transformed cancer treatment, but not all patients respond. In pleural mesothelioma, a rare and aggressive cancer, only a small group of patients benefit. Doctors still cannot tell in advance who will respond.
A new study published in Nature Genetics identifies groups of patients who are more likely to respond and clues to why only some tumors respond.
“Immunotherapy works, but only for a subset of pleural mesothelioma patients,” said study senior author Michele Ceccarelli, a computational oncology researcher at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. “Our goal was to identify who has the best chance to respond.”
Understanding Pleural Mesothelioma
Pleural mesothelioma is a cancer in the lining of the lungs that affects about 3,000 people in the United States each year. Most cases are linked to asbestos exposure at work decades earlier. Many people do not receive a diagnosis until the cancer has already advanced. They live only about one to two years after diagnosis, even with treatment.
“We are starting to understand the biology behind this negative response,” said study co-author Teresa Maria Rosaria Noviello, Ph.D., Sylvester researcher and assistant professor of biostatistics at the Miller School, who completed this work as a postdoctoral fellow in Ceccarelli’s lab. “Knowing that opens the door to new strategies for patients who do not benefit today.”
Looking Beyond Standard Markers
The researchers analyzed tumor samples across multiple centers from 91 pleural mesothelioma patients who had been treated with immunotherapy. They first examined tumor mutational burden biomarkers, a measure of how many mutations are present in a tumor and often used to predict response to immunotherapy.
“We expected standard biomarkers to help guide treatment, but they did not,” Dr. Noviello said. “That pushed us to look at the tumor in a different way.”
The team next examined how genes are turned on or off. The process is called DNA methylation. When Noviello and her colleagues grouped tumors by methylation pattern, they identified four subsets, ranging from low to very high methylation.
These groups closely matched patient response and survival. Patients in the low-methylation group had the best outcomes, with a median survival of about 27 months. Patients in the highest-methylation group had a median survival of about nine months. None were alive at three years.
The immune system helped explain the difference. Tissue and gene analyses showed that low-methylation tumors were rich in immune cells. Highly methylated tumors had far fewer of these cells.
“Each layer of information — mutations, gene activity, immune cells — can look separate. But when you put them together, you start to see the full picture,” Dr. Noviello said. “These features can make some tumors more visible to the immune system, while others remain hidden. And that difference can shape how well immunotherapy works.”
From Insight to Potential Treatment
Building on these findings, the team developed a web-based tool that allows researchers and clinicians to classify tumors based on their methylation data and estimate how likely they are to respond to immunotherapy.
In testing, the model identified patients most likely to benefit. While this type of methylation testing is not yet part of routine care, similar tests exist and could be adapted to measure the specific regions identified in this study.
“The goal is to make this information usable in practice,” Ceccarelli said. “We want clinicians to better estimate whether a patient is likely to respond.”
The team also explored whether these patterns could be detected without a tumor biopsy. In a small group of patients, they studied blood samples and found the same methylation signals, suggesting the possibility of a less invasive test.
Toward New Combination Treatment Strategies
The findings also point to new treatment strategies. Because higher methylation subsets showed lower immune activity, the researchers think that drugs called DNA demethylating agents could help “unmask” tumors.
“If a tumor is not responding, we may be able to change that,” Dr. Noviello said. “Combining immunotherapy with drugs that alter methylation could make these tumors more visible.”
The researchers emphasize that this is early-stage work. The study included a relatively small number of patients, so the findings need to be validated in larger groups. Next steps include looking at these same signals in other cancer types and testing drug combinations in clinical trials.
“This kind of work depends on integrating different types of data and working closely with clinicians,” Ceccarelli said. “The collaborative environment at Sylvester supports this type of integrative research, helping us take meaningful steps forward in a very challenging disease.”
More from Sylvester Comprehensive Cancer Center
A mother-daughter initiative, “More for Mom,” delivers comfort and support to chemotherapy patients at Sylvester Comprehensive Cancer Center.
Team‑based care at Sylvester Comprehensive Cancer Center is changing how multiple myeloma is thought of and treated.
A Hirshberg Foundation grant supports a University of Miami study exploring a new way to anchor immune cells inside pancreatic tumors.
The pioneer of cancer immunotherap, joins Sylvester Comprehensive Cancer Center to expand clinical trials and advance patient care.
Tags: cancer research, Department of Public Health Sciences, Dr. Teresa Maria Rosaria Noviello, immunotherapy, mesothelioma, Michele Ceccarelli, public health sciences