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

Hua, 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

Cancer cell, 2022-12, Vol.40 (12), p.1600-1618.e10 [Periódico revisado por pares]

United States: Elsevier Inc

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Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop
Autor: Hua, 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
Assuntos: antiangiogenic immunotherapy ; Endothelial Cells ; endothelial fate mapping ; high-endothelial venule ; Humans ; immune checkpoint blockade ; Immunotherapy ; Life Sciences ; Lymph Nodes ; lymphotoxin beta receptor ; multiplex immunohistochemistry ; Neoplasms - pathology ; pTEX ; single-cell RNA sequencing ; tertiary lymphoid structure ; tTEX ; Venules - pathology
É parte de: Cancer cell, 2022-12, Vol.40 (12), p.1600-1618.e10
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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. [Display omitted] •Tumor endothelial cells dynamically transition into high-endothelial venules (TU-HEVs)•TU-HEVs require NK and CD8 T cell-derived signals for induction and maintenance•TU-HEV niches enable PD1+TCF1+ progenitor CD8 T cell expansion into effector T cells•The presence of a human HEV signature in tumors correlates with response to ICB therapy Hua et al. reveal that effective antiangiogenic immunotherapy differentiates postcapillary venules into high-endothelial venules (HEVs) by lymphotoxin beta receptor activation emanating from CD8 T and NK cell-derived signals. TU-HEVs establish perivascular niches in which TCF1+PD1+ lymphocytes expand and produce cytotoxic PD1+TIM3+ lymphocytes that may facilitate anti-tumoral immunity.
Editor: United States: Elsevier Inc
Idioma: Inglês;Francês

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

United States: Elsevier Inc

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