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-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEVs), which generate permissive TA-TLS-like lymphocyte niches with PD1 neg and PD1 + TCF1 + CD8 T cell progenitors that differentiate into GrzB + TCF1 neg TIM3 + PD1 + CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop. In Brief Hua &amp; Vella et al. reveal that effective antiangiogenic immunotherapy transitions postcapillary venules into inflamed high-endothelial venules (HEV), sustained by CD8 T and NK cell-derived signals through a feed-forward loop. Thereby, tumoral HEVs establish perivascular niches in which TCF1 + PD1+ lymphocytes expand and produce cytolytic PD1+ TIM3+ CD8 T cells that facilitate anti-tumoral immunity. Highlights High endothelial venule induction by anticancer immunotherapies generates perivascular immune niches permissive for TCF1 + PD1 + CD8 progenitor T cell expansion and production of TCF1 neg PD1 + TIM3 + CD8 effector T cells Tumoral high-endothelial venules exhibit characteristics of inflamed lymph node HEVs and postcapillary venules Postcapillary venules dynamically transdifferentiate into high-endothelial venules in tumors, which requires continuous signals from surrounding immune cells CD8 and NK cells drive tumoral high-endothelial venule formation during antiangiogenic immunotherapies in a feed-forward loop via lymphotoxin beta receptor signaling

Anticancer immunotherapies transition postcapillary venules into high-endothelial venules that generate TCF1+ T lymphocyte niches through a feed-forward loop