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

• Published in: Cancer cell Vol. 40; no. 12; pp. 1600 - 1618.e10
• Main Authors: 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
• Format: Journal Article
• Language: English; French
• Published: United States Elsevier Inc 12.12.2022; Elsevier
• Series: Cancer Cell
• Subjects: 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; lymphotoxin beta receptor; single-cell RNA sequencing; tertiary lymphoid structure; high-endothelial venule; multiplex immunohistochemistry; antiangiogenic immunotherapy; pTEX; t; tTEX; endothelial fate mapping; immune checkpoint blockade; pT(EX); tT(EX)
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2022.11.002

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.