Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop
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, a...
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Published in | Cancer cell Vol. 40; no. 12; pp. 1600 - 1618.e10 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English French |
Published |
United States
Elsevier Inc
12.12.2022
Elsevier |
Series | Cancer Cell |
Subjects | |
Online Access | Get full text |
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Summary: | 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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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-6108 1878-3686 |
DOI: | 10.1016/j.ccell.2022.11.002 |