IL-17 Activity Identifies Ovarian Cancer Subtype Responsive to Immunotherapy

A research team led by Kindai University has discovered that a distinct subtype of clear cell ovarian carcinoma, characterized by high activity of the inflammatory protein IL-17, responds to immune checkpoint inhibitor therapy. Clear cell ovarian cancer accounts for roughly one-quarter of ovarian cancers in Japan and has been largely resistant to standard chemotherapy and immunotherapy, which generally show limited benefit in ovarian cancer overall. The findings, published in Molecular Cancer, are based on analyses of 180 human tumor samples and complementary mouse models.

The study revealed that approximately 5% of clear cell ovarian cancers exhibit an inflammatory signature driven by IL-17, marked by immune cell infiltration and activation within the tumor microenvironment. This signature emerged independently of conventional biomarkers such as microsatellite instability and high tumor mutational burden, suggesting IL-17 could serve as a new predictive biomarker for immunotherapy response.

Using mouse models replicating human clear cell ovarian cancer, the researchers demonstrated that IL-17 acts directly on cancer cells, activating the NF-κB signaling pathway. This triggers the cancer cells to produce chemokines that recruit and activate immune cells, converting an immunologically "cold" tumor into one permissive to immune attack.

In mice with an IL-17-driven inflammatory microenvironment, treatment with an anti-PD-L1 antibody led to increased immune cell infiltration, sustained anti-tumor immune cell function, and prolonged survival. No survival benefit was observed in the absence of immunotherapy, indicating that IL-17 marks responsiveness to treatment rather than inherent prognosis.

Single-cell analysis confirmed that the recruited immune cells retained their ability to attack the tumor rather than becoming dysfunctional. The researchers suggest this mechanism may extend beyond clear cell ovarian cancer to other tumor types where cancer cell-intrinsic inflammation shapes immunotherapy efficacy.

Lead author Kosuke Murakami, a lecturer at Kindai University Faculty of Medicine, noted that while the responsive subset is small, identifying these patients could enable personalized immunotherapy for a disease with few options. The work involved collaboration with RIKEN Center for Integrative Medical Sciences and the Department of Immunology at Kindai University.

The study provides a mechanistic explanation for why a minority of clear cell ovarian cancer patients respond to immunotherapy and offers a pathway to select those patients in advance. Further research is needed to validate IL-17 as a clinical biomarker and to explore therapeutic strategies that could induce this inflammatory state in non-responsive tumors.