Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer.

Autor:	Launonen IM; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Erkan EP; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Niemiec I; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Junquera A; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Hincapié-Otero M; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Afenteva D; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Liang Z; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Salko M; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Szabo A; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Perez-Villatoro F; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Falco MM; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Li Y; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Micoli G; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Nagaraj A; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Haltia UM; 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., Kahelin E; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.; Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital., Oikkonen J; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Hynninen J; Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland., Virtanen A; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.; Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital., Nirmal AJ; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, USA., Vallius T; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, USA.; Ludwig Center at Harvard., Hautaniemi S; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland., Sorger P; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, USA., Vähärautio A; Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.; Foundation for the Finnish Cancer Institute, Finland., Färkkilä A; 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, Finland.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 20. Date of Electronic Publication: 2024 Mar 20.
DOI:	10.1101/2024.03.19.585657
Abstrakt:	To uncover the intricate, chemotherapy-induced spatiotemporal remodeling of the tumor microenvironment, we conducted integrative spatial and molecular characterization of 97 high-grade serous ovarian cancer (HGSC) samples collected before and after chemotherapy. Using single-cell and spatial analyses, we identify increasingly versatile immune cell states, which form spatiotemporally dynamic microcommunities at the tumor-stroma interface. We demonstrate that chemotherapy triggers spatial redistribution and exhaustion of CD8+ T cells due to prolonged antigen presentation by macrophages, both within interconnected myeloid networks termed "Myelonets" and at the tumor stroma interface. Single-cell and spatial transcriptomics identifies prominent TIGIT-NECTIN2 ligand-receptor interactions induced by chemotherapy. Using a functional patient-derived immuno-oncology platform, we show that CD8+T-cell activity can be boosted by combining immune checkpoint blockade with chemotherapy. Our discovery of chemotherapy-induced myeloid-driven spatial T-cell exhaustion paves the way for novel immunotherapeutic strategies to unleash CD8+ T-cell-mediated anti-tumor immunity in HGSC. Competing Interests: Declaration of interests The authors declare no competing interests
Databáze:	MEDLINE
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