Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1 + T lymphocyte niches through a feed-forward loop.
Résumé
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 and
cellular immune responses against cancers, is associated with good prognosis, and they have recently been
detected 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-modulating
therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs)
via lymphotoxin/lymphotoxin beta receptor (LT/LTbR) signaling. In turn, tumor HEVs boost intratumoral
lymphocyte influx and foster permissive lymphocyte niches for PD1 and PD1+
TCF1+ CD8 T cell progenitors
that 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 system
through a feed-forward loop.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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