Findings could suggest new targets for immunotherapy
A recent study led by researchers at TGen, part of City of Hope, has revealed that dysfunctional gene splicing in a rare type of ovarian cancer may increase the likelihood of these cancers responding to immunotherapy treatments. The study focused on small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive cancer.
The researchers found that the unusual splicing process in SCCOHT tumors could serve as a model for understanding how other similar tumors might provoke a targetable immune response.
SCCOHT tumors are driven by loss of function in the protein SMARCA4, which is part of a larger protein complex called SWI/SNF. This complex plays a key role in gene expression during the process that transcribes DNA into the RNA template for new proteins. Tumor cells without functional SMARCA4 retain genetic material called introns that would normally be spliced out of the RNA, the researchers report in the journal Cancer Research.
“As a result of the dysfunctional splicing, tumor cells produce new proteins that prompt immune cells to recognize tumor cells as foreign. In the lab, these aberrant proteins caused human immune cells called T cells to multiply and activate immune factors,” said Patrick Pirrotte, Ph.D., associate professor at TGen, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, and senior author of the study. “The findings could lead to the development of more targeted immune therapies against the cancer,” he added.
While DNA sequence mutations in tumors are generally considered the primary source of neoantigens, the molecules immune cells recognize as foreign on cancer cells, the study results support a more recent hypothesis: that some tumors produce neoantigens through splicing. This could suggest that tumors with few mutations, such as SCCOHT, may still respond to immune therapies, even if they don’t appear to be a good fit for immunotherapy based on prior knowledge.
“SCCOHT is a rare and extremely aggressive ovarian cancer that primarily affects young women, often in their twenties, though cases have been reported at much younger ages. This cancer has a poor prognosis and no effective standard treatments. This research provides valuable opportunities to identify new therapeutic targets for this devastating disease,” said TGen President & Research Director, Jeffrey M. Trent, Ph.D., one of the paper’s authors and scientist who led earlier work on the discovery of the genetic driver for this cancer and development of a potential therapeutics.
Although only 300 to 400 cases of SCCOHT have been reported since 1976, the researchers were able to use it as a simple model to observe how disruptions in the SWI/SNF complex affect splicing and the production of tumor neoantigens, suggesting that this model could have much broader implications.
“SCCOHT was the perfect model because the tumors appear to have only one mutation, in the SMARCA4 gene,” said Elizabeth Raupach, Ph.D., a research scientist at Mayo Clinic and the study’s first author. “However, about 25 percent of cancers have mutations in other SWI/SNF complex members. Our findings additionally linked splicing dysregulation with SWI/SNF complex members across many tumors in The Cancer Genome Atlas, demonstrating that these findings are relevant to other cancers.”
Additionally, this study provides an in-depth characterization of the SWI/SNF complex and could serve as a valuable resource for future cancer research and the development of new immune-based therapies.
The National Institutes of Health, Baylor Scott & White Research Institute, Markel Friedman Accelerator Fund and Ovarian Cancer Research Alliance funded this research.
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Becky Ham
Posted on Friday, May 23, 2025