Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer

Abstract

Anti-tumor immunity is crucial for high-grade serous ovarian cancer (HGSC) prognosis, yet its adaptation upon standard chemotherapy remains poorly understood. Here, we conduct spatial and molecular characterization of 117 HGSC samples collected before and after chemotherapy. Our single-cell and spatial analyses reveal increasingly versatile immune cell states forming spatiotemporally dynamic microcommunities. We describe Myelonets, networks of interconnected myeloid cells that contribute to CD8⁺ T cell exhaustion post-chemotherapy and show that M1/M2 polarization at the tumor-stroma interface is associated with CD8⁺ T cell exhaustion and exclusion, correlating with poor chemoresponse. Single-cell and spatial transcriptomics reveal prominent myeloid-T cell interactions via NECTIN2-TIGIT induced by chemotherapy. Targeting these interactions using a functional patient-derived immuno-oncology platform demonstrates that high NECTIN2-TIGIT signaling in matched tumors predicts responses to immune checkpoint blockade. Our discovery of clinically relevant myeloid-driven spatial T cell exhaustion unlocks immunotherapeutic strategies to unleash CD8⁺ T cell-mediated anti-tumor immunity in HGSC.