Scientists at The Wistar Institute have identified a new biological mechanism behind chemotherapy resistance in high-grade serous carcinoma, the most common and deadly subtype of ovarian cancer. According to a study published in The Journal for ImmunoTherapy of Cancer, chemotherapy triggers an inflammatory cascade that recruits protective immune cells into the tumor microenvironment, effectively shielding cancer cells from subsequent treatment.
Shifting the Medical Paradigm from Cancer Cells to Tumor Immunology
For decades, researchers viewed resistance to chemotherapy as an intrinsic problem of cancer cells undergoing genetic or transcriptional alterations. However, findings from the Wistar research team indicate that microenvironmental mechanisms play a major role, reframing the challenge as an immunology problem. “The treatment meant to kill the tumor can trigger inflammatory responses that help it survive,” said Nan Zhang, Ph.D., assistant professor in the Ellen and Ronald Caplan Cancer Center’s Molecular and Cellular Oncogenesis Program and senior author on the study.
While prior genomic research found limited divergence between primary and recurrent tumors, scientists recognized that the surrounding tumor microenvironment undergoes significant shifts. To investigate these changes, Zhang collaborated with gynecology pathologists at the Kyoto University Graduate School of Medicine. Using publicly available datasets, the research team compared patient tumor samples collected before and after chemotherapy.
Did you know? High-grade serous carcinoma patients often respond well to first-line chemotherapy, but the vast majority eventually experience recurrent disease that resists subsequent drug regimens.
How Interleukin-1 Beta and Neutrophils Drive Drug Resistance
The analysis revealed that interleukin-1 beta (IL-1β)—a signaling protein released by the body to promote inflammation—was significantly elevated following chemotherapy, particularly in patients whose tumors responded poorly to treatment. Funding from the Concern Foundation, the V Foundation for Cancer Research, and the Ovarian Cancer Research Alliance supported this investigation.
To test the functional significance of IL-1β, researchers utilized genetically engineered murine models lacking the ability to produce or respond to the protein. When administered chemotherapy, these modified models experienced tumor shrinkage, whereas models with normal immune systems retained treatment resistance. Tracing the pathway further, the team discovered that IL-1β binds to structural cells within tumors, prompting them to release chemical signals that recruit white blood cells known as neutrophils.
Once inside the tumor, these neutrophils protect cancer cells through two distinct actions: they exhaust cancer-fighting T cells and they undergo NETosis. During NETosis, neutrophils rupture and release web-like structures called neutrophil extracellular traps (NETs). Laboratory tests confirmed that NETs diminish the effectiveness of chemotherapy drugs, while blocking NET formation successfully restores drug sensitivity. Examination of patient tumor samples corroborated the preclinical models, showing increased neutrophil infiltration and NET formation following chemotherapy.
Translating Preclinical Discoveries Into Clinical Strategies
The discovery opens up potential new pathways for patient care because drugs capable of blocking the IL-1β pathway already exist in clinical use for other diseases. “IL-1β therapies are already out there, and some are actually clinically approved for other conditions. So there is potential for these to be leveraged in this new context,” said Marlaine Soliman, a third-year doctoral student in the Immunology Graduate Group at the University of Pennsylvania and co-author on the study.
Researchers are also exploring combination approaches involving immune checkpoint inhibitors designed to reawaken exhausted T cells. Pairing checkpoint inhibitors with IL-1β-targeted therapies could provide another avenue to restore chemotherapy effectiveness in recurrent cases.
Open questions remain for the team. Scientists have not yet determined the precise trigger for increased IL-1β production after chemotherapy, nor have they fully mapped how NETs impair drug sensitivity at the molecular level. Soliman is actively investigating these questions as part of her doctoral thesis research in the Zhang laboratory, alongside evaluating whether T cells become truly exhausted and if checkpoint inhibitors can reverse that exhaustion.
“It’s important to recognize that this is a complex tumor microenvironment, and this pathway is likely not the only reason patients experience chemoresistance,” Soliman noted. “But if you can significantly reduce resistance, that’s important. At the end of the day, it’s about how patients who have already gone through treatment once could get through it again if their cancer recurs, but with even better outcomes.”
Frequently Asked Questions
Q: What causes chemotherapy resistance in ovarian cancer according to this study?
A: According to researchers at The Wistar Institute, chemotherapy triggers an inflammatory cascade—specifically releasing the protein IL-1β—which recruits neutrophils that protect cancer cells and exhaust T cells.
Q: Can existing drugs target this newly discovered pathway?
A: Yes. Study authors note that IL-1β-blocking therapies are already clinically approved for other diseases and could potentially be repurposed for ovarian cancer treatment.
Q: What are neutrophil extracellular traps (NETs)?
A: NETs are web-like structures released when neutrophils undergo a process called NETosis inside tumors. Laboratory tests show these structures reduce the effectiveness of chemotherapy drugs.
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