Zusammenfassung
The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the forma-tion 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. ...
Zusammenfassung
The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the forma-tion 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 aggre-gates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate map-ping, 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/LTbR) 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.