VISTA+ Neutrophils Contribute to Platinum Resistance by Suppressing CD8+ T Cells in High-Grade Serous Ovarian Cancer.

Abstract

Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with platinum resistance and poor outcomes in high-grade serous ovarian cancer (HGSOC), but the biological basis of this association remains unclear. We retrospectively analyzed 434 patients with HGSOC treated with platinum-based chemotherapy and found that elevated NLR was an independent predictor of platinum resistance. To further investigate the cellular basis of this association, we performed immunohistochemistry (IHC), proteomic profiling, and single-cell RNA sequencing on patient samples. These analyses identified a distinct subpopulation of V-domain immunoglobulin suppressor of T-cell activation-positive neutrophils (VISTA+Neus) enriched in resistant tumors. High VISTA+Neus density was linked to shorter progression-free survival and showed greater predictive value for resistance than total neutrophils. Spatial and multicolor IHC analyses further showed that VISTA+Neus were associated with reduced CD8+ T-cell infiltration and cytotoxic features. Functional validation in an immunocompetent mouse model showed that anti-VISTA plus cisplatin reduced tumor growth, decreased neutrophil abundance, and increased CD8+ T-cell infiltration and granzyme B expression. CD8+ T-cell depletion markedly attenuated the therapeutic benefit of the combination. These findings support VISTA+Neus as a potential immunosuppressive neutrophil subset associated with platinum resistance and CD8+ T-cell suppression in HGSO, and support further investigation of VISTA-targeted strategies and the potential biomarker value of VISTA+Neus.