High endothelial venules in cancer: Regulation, function, and therapeutic implication

The lack of sufficient intratumoral CD8⁺ T lymphocytes is a significant obstacle to effective immunotherapy in cancer. High endothelial venules (HEVs) are organ-specific and specialized postcapillary venules uniquely poised to facilitate the transmigration of lymphocytes to lymph nodes (LNs) and other secondary lymphoid organs (SLOs). HEVs can also form in human and murine cancer (tumor HEVs [TU-HEVs]) and contribute to the generation of diffuse T cell-enriched aggregates or tertiary lymphoid structures (TLSs), which are commonly associated with a good prognosis. Thus, therapeutic induction of TU-HEVs may provide attractive avenues to induce and sustain the efficacy of immunotherapies by overcoming the major restriction of T cell exclusion from the tumor microenvironment. In this review, we provide current insight into the commonalities and discrepancies of HEV formation and regulation in LNs and tumors and discuss the specific function and significance of TU-HEVs in eliciting, predicting, and aiding anti-tumoral immunity.