Abstract A34: Therapeutic induction of High Endothelial Venules in cancer generates TCF1+ lymphocyte niches

Abstract 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 multiplex immunohistochemistry, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEV), which predominantly generate permissive TA-TLS-like lymphocyte niches. These HEV+ immune niches entail PD1neg and PD1+TCF1+CD8+ progenitor cells that differentiate into cytotoxic TCF1neg TIM3+ PD1+ CD8 effector cells and migrate into the tumor core. Congruently, TU-HEV signatures correlate with response to ICB therapies in several human tumor types. In line with these observations, TU-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the immune system through a feed-forward loop. Citation Format: Gerlanda Vella, Yichao Hua, Florian Rambow, Elizabeth Allen, Asier Antoranz Martinez, Pascal Merchiers, Francesca Bosisio, Giuseppe Floris, Akira Takeda, Sirpa Jalkanen, Maija Hollmén, Jean-Christophe Marine, Susan Schlenner, Gabriele Bergers. Therapeutic induction of High Endothelial Venules in cancer generates TCF1+ lymphocyte niches [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A34.