Launonen et al. explored the dynamic remodeling of HGSC TME under platinum-based chemotherapy and identified myelonets – spatially confined networks of interconnected myeloid cells – as key drivers of T cell exhaustion. Chemotherapy induced T cell infiltration and exhaustion, particularly within myeloid-rich areas. At the tumor–stroma interface, M2 macrophages excluded T cell interaction with tumor cells, while M1 macrophages at myelonets induced exhaustion through NECTIN2–TIGIT signaling. Targeting the chemotherapy-induced TIGIT–NECTIN2 axis in patient-derived 3D cultures reactivated T cells, highlighting a therapeutic opportunity.
Contributed by Shishir Pant
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.
Author Info: (1) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (2) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (3) Resear
Author Info: (1) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (2) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (3) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (4) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (5) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (6) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (7) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (8) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (9) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (10) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (11) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (12) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (13) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (14) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (15) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (16) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Department of Oncology, Clinical Trials Unit, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. (17) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland. (18) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (19) Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland. (20) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland. (21) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. (22) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA. (23) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland. (24) Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA. (25) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Foundation for the Finnish Cancer Institute, Helsinki, Finland. Electronic address: anna.vaharautio@helsinki.fi. (26) Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Department of Oncology, Clinical Trials Unit, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland; Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland. Electronic address: anniina.farkkila@helsinki.fi.
