Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1 ⁺ T lymphocyte niches through a feed-forward loop.

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Hua, Y. | Vella, G. | Rambow, F. | Allen, E. | Antoranz Martinez, A. | Duhamel, Marie | Takeda, A. | Jalkanen, S. | Junius, S. | Smeets, A. | Nittner, D. | Dimmeler, S. | Hehlgans, T. | Liston, A. | Bosisio, F. M. | Floris, G. | Laoui, D. | Hollmén, M. | Lambrechts, D. | Merchiers, P. | Marine, J. C. | Schlenner, S. | Bergers, G.

Edité par CCSD ; Elsevier -

International audience. The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral andcellular immune responses against cancers, is associated with good prognosis, and they have recently beendetected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulatingtherapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs)via lymphotoxin/lymphotoxin beta receptor (LT/LTbR) signaling. In turn, tumor HEVs boost intratumorallymphocyte influx and foster permissive lymphocyte niches for PD1 and PD1+TCF1+ CD8 T cell progenitorsthat differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cellderived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune systemthrough a feed-forward loop.

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