Immunotherapy has given some patients a better outcome with mesothelioma, an aggressive cancer in the lining around the lungs that has been linked to asbestos exposure. The individualized therapy can stimulate the body's immune system to attack cancer cells and prolong life. But it doesn't always work, and some patients experience significant side effects. 

Now, Mayo Clinic Center for Individualized Medicine researchers may have discovered a genomic signature to predict which patients with mesothelioma could benefit from immunotherapy.  

The new study, published in the Journal of Thoracic Oncology and led by Aaron Mansfield, M.D., co-director of Mayo Clinic Precision Cancer Therapeutics, provides insight for a new approach in guiding the use of immunotherapy. 

"We're now a step closer to understanding the unique genomics of mesothelioma, compared to other tumors," says Dr. Mansfield. "We're also a step closer to being able to figure out who's most likely to benefit from immunotherapy." 

Mesothelioma is a rare cancer that develops in the thin membranes of the chest and abdomen, and it is most commonly associated with inhaling asbestos fibers. These fibers can be found in insulation, vinyl tiles, roofing and paint. Despite decades of regulations to limit asbestos exposure, approximately 3,000 people in the U.S. are diagnosed with mesothelioma every year. 

Discovery points to new individualized approach 

One of the leading biomarkers for determining which patients receive immunotherapy for various cancers is related to the number of gene mutations in a patient's cancer tumor. This assumes that a high number of mutations are more likely to be recognized as abnormal by the body's immune system. But Dr. Mansfield says many patients with mesothelioma also benefit from immunotherapy, despite its usual low number of mutations.   

"This discrepancy led us to search for other explanations for what activates or prevents a response to immunotherapy in patients with mesothelioma," Dr. Mansfield explains. 

For the study, Dr. Mansfield and his team, in collaboration with Netherlands Cancer Institute researchers, investigated complex mutations in large fragments of DNA from 44 patients with mesothelioma before they received immunotherapy. Using an extensive sequencing method, the researchers analyzed the chromosomal strands to see if they had been rearranged, broken apart or joined together.  

"Instead of just analyzing a single point mutation, we can tell when the arms of the DNA are switching around," Dr. Mansfield explains. "Those genetic mutations are known as chromosomal rearrangements." 

Dr. Mansfield says a chromosomal rearrangement by itself is not a perfect predictor of response to immunotherapy. Rather, what also matters is whether the tumor cells present the resultant abnormal proteins to the immune system.

Dr. Mansfield explains that the cells in the body present protein fragments on their surface that can trigger the immune system. But some tumors stop presenting protein fragments to hide from the immune system and not be attacked.

"To be recognized by the immune system, the tumor cells need to present the mutant proteins to alert the immune system to the tumor so that the immune system attacks and eliminates it. This is like turning on a signal. A mutation could otherwise escape recognition from our immune system's surveillance mechanisms," he says.  

Overall, the researchers discovered that the combination of chromosomal rearrangements and the ability of tumor cells to present mutant proteins was a telltale sign to indicate which patients were most likely to benefit from immunotherapy.

The findings build on the team's previous studies that show how chromosomal rearrangements have neoantigenic potential, meaning they can help the body make an immune response against cancer cells.

The team also plans to explore this sequencing concept in other tumors.

This study was financially supported by Mayo Clinic's Center for Individualized Medicine, The Mark Foundation for Cancer Research ASPIRE Awards, National Cancer Institute grant R21 CA251923, and the Barry Family. 

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