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

Julkaisun tekijätHua Yichao, Vella Gerlanda, Rambow Florian, Allen Elizabeth, Antoranz Martinez Asier, Duhamel Marie, Takeda Akira, Jalkanen Sirpa, Junius Steffie, Smeets Ann, Nittner David, Dimmeler Stefanie, Hehlgans Thomas, Liston Adrian, Bosisio Francesca Maria, Floris Giuseppe, Laoui Damya, Hollmén Maija, Lambrechts Diether, Merchiers Pascal, Marine Jean-Christophe, Schlenner Susan, Bergers Gabriele

KustantajaCell Press


JournalCancer Cell

Tietokannassa oleva lehden nimiCancer Cell






Rinnakkaistallenteen osoite


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/LTβR) 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 cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

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Last updated on 2023-15-06 at 16:05