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

Launonen, I.-M. P.; Erkan, E. P.; Niemiec, I.; Junquera, A.; Hincapie-Otero, M.; Afenteva, D.; Liang, Z.; Salko, M.; Szabo, A.; Perez-Villatoro, F.; Falco, M. M.; Li, Y.; Micoli, G.; Nagaraj, A.; Haltia, U.-M.; Kahelin, E.; Oikkonen, J.; Hynninen, J.; Virtanen, A.; Nirmal, A. J.; Vallius, T.; Hautaniemi, S.; Sorger, P. K.; Vaharautio, A.; Farkkila, A.

doi:10.1101/2024.03.19.585657

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bioRxiv · 10.1101/2024.03.19.585657

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

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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.

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Launonen, I.-M. P., Erkan, E. P., Niemiec, I., Junquera, A., Hincapie-Otero, M., Afenteva, D., Liang, Z., Salko, M., Szabo, A., Perez-Villatoro, F., Falco, M. M., Li, Y., Micoli, G., Nagaraj, A., Haltia, U.-M., Kahelin, E., Oikkonen, J., Hynninen, J., Virtanen, A., Nirmal, A. J., Vallius, T., Hautaniemi, S., Sorger, P. K., Vaharautio, A., Farkkila, A.. 2024-03-20. Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer. https://doi.org/10.1101/2024.03.19.585657

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