Unraveling the ontogeny, regulation and function of intratumoral high endothelial venules to enhance immunotherapy

Recent results from our laboratory supported the notion that therapeutically induced high-endothelial venules (HEVs) promote antitumor immunity by recruiting lymphocytes into the tumor, thus allowing the local generation of cancerous tissue-destroying T lymphocytes. In this study, we aimed to unravel the ontogeny, regulation, and function of intratumoral HEVs (TU-HEVs). Single-cell transcriptomics revealed that TU-HEVs exhibit a hybrid phenotype of tumor endothelial cells (ECs) and lymph node HEVs. Mouse and human TU-HEVs share conserved signatures, and the presence of a TU-HEV gene signature was associated with a better response to immune checkpoint blockade therapies in melanoma and NSCLC patients. TU-HEVs are highly dynamic and transdifferentiated from post-capillary venules within days of anti-angiogenic immunotherapy and rapidly reverted to non-HEV ECs, of which few even lost their endothelial fate after treatment cessation. EC- specific LTβR signaling was found to be essential for TU-HEV induction. Tumor HEVs facilitate lymphocyte infiltration and contribute to the formation of tertiary lymphoid-like structures, thereby creating an immunostimulatory microenvironment.