IL-17–Driven Tumor Cell–Intrinsic Inflammatory Programming Creates an Immunotherapy-Permissive Microenvironment in Ovarian Clear Cell Carcinoma [scRNA-Seq]
Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer with limited effective therapeutic options. Although immune checkpoint inhibitors (ICIs) have shown little benefit in unselected ovarian cancer populations, clinical activity observed in a subset of OCCC patients suggests the presence of a histotype-specific immune vulnerability that remains poorly defined. To elucidate this biology, we integrated transcriptomic analyses from multiple independent human OCCC cohorts with immunohistochemical profiling and mechanistic studies using an immunocompetent syngeneic OCCC mouse model. Tumor cell–intrinsic and microenvironmental responses to IL-17 were investigated through in vitro stimulation assays, in vivo IL-17 administration, single-cell RNA sequencing of tumor-infiltrating T cells, and immune checkpoint blockade in a Th17-biased partial chimera model. OCCC was characterized as an IL-6–high tumor entity with a globally immune-sparse but CD4? T-cell–skewed tumor immune microenvironment. Transcriptomic analyses identified a Th17-associated program marked by elevated RORC expression in a subset of tumors. Across large clinical cohorts, an IL17A^high subset demonstrated a T cell–inflamed gene expression profile independent of microsatellite instability and tumor mutational burden; however, this phenotype was not associated with survival in untreated disease. Mechanistically, IL-17 directly activated NF-?B–dependent inflammatory programs in OCCC tumor cells, inducing cytokines involved in T-cell recruitment and activation. In vivo, IL-17 remodeled the immune microenvironment, increasing infiltration and activation of both CD4? and CD8? T cells. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4? T cells and cytotoxic, non-terminally exhausted CD8? T cells. Consistent with these findings, anti–PD-L1 therapy significantly improved survival exclusively in Th17-biased partial chimera mice. Collectively, these results demonstrate that a Th17-biased, IL-17–responsive immune contexture in OCCC engages tumor cell–intrinsic NF-?B inflammatory signaling to prime antitumor T-cell states and enable checkpoint blockade efficacy. This immune biology is predictive rather than prognostic, supporting a biomarker-driven immunotherapy strategy for OCCC within otherwise ICI-refractory ovarian cancer. Overall design: Tumor tissues were collected from syngeneic murine ovarian clear cell carcinoma models established in immunocompetent mice. In selected experiments, tumors were generated under IL-17 or control conditions. Single-cell suspensions were prepared from excised tumors and processed for single-cell RNA sequencing using the BD platform. The study aimed to determine how an IL-17–enriched tumor microenvironment shapes immune cell infiltration, activation states, and immune checkpoint expression. Comparative analyses were performed between IL-17–exposed and control tumors.