Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer
: Launonen, Inga-Maria; Niemiec, Iga; Hincapié-Otero, María; Erkan, Pekcan Erdogan; Junquera, Ada; Afenteva, Daria; Falco, Matias M.; Liang, Zhihan; Salko, Matilda; Chamchougia, Foteini; Szabo, Angela; Perez-Villatoro, Fernando; Li, Yilin; Micoli, Giulia; Nagaraj, Ashwini; Haltia, Ulla-Maija; Kahelin, Essi; Oikkonen, Jaana; Hynninen, Johanna; Virtanen, Anni; Nirmal, Ajit J.; Vallius, Tuulia; Hautaniemi, Sampsa; Sorger, Peter K.; Vähärautio, Anna; Färkkilä, Anniina
Publisher: Cell Press
: 2024
: Cancer Cell
: Cancer cell
: Cancer Cell
: 42
: 12
: 2045
: 2063.e10
: 1535-6108
: 1878-3686
DOI: https://doi.org/10.1016/j.ccell.2024.11.005
: https://doi.org/10.1016/j.ccell.2024.11.005
: https://research.utu.fi/converis/portal/detail/Publication/477844218
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.
:
This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 667403 for HERCULES and no. 965193 for DECIDER. This study was co-funded by the European Union (ERC, SPACE 101076096 and ERC STRONGER 101125261). Views and opinions expressed are however those of the author(s) only and do not necessarily
reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. Funding was also received from the Sigrid Juse´ lius Foundation, Research Council of Finland (1339805 and 350396), Cancer Foundation Finland, Finnish Medical, Ida Montini Emil Aaltonen, Biomedicum, K. Albin Johanssons, and Instrumentarium Foundations, Finland, and HORIZON-MSCA-2021- PF, European Commission (M.M.F.: 101067835), Ludwig Cancer Research Center at Harvard Medical School (P.K.S) and R00CA256497 (A.J.N.) from NCI.
