Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer.
bioRxiv
; 2024 Mar 20.
Article
in En
| MEDLINE
| ID: mdl-38562799
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
BioRxiv
Year:
2024
Document type:
Article
Affiliation country:
Finland
Country of publication:
United States