THE ROLE OF TUMOR-ASSOCIATED HIGH ENDOTHELIAL VENULES IN IMMUNE CELL RECRUITMENT AND PANCREATIC TUMOR GROWTH

High endothelial venules (HEVs) serve as the primary portal for T cell homing. Therefore, tumor-associated HEVs (TA-HEVs) play a fundamental role in regulating tumor immunity. However, the key signaling molecules that control their formation, as well as their causal role in tumor development, remain to be fully explored. Here, we demonstrate that Interferon-gamma (IFNγ) secreted by tumor-infiltrating lymphocytes (TILs), is fundamental for TA-HEVs formation. TILs stimulate one another through the TNFSF14 (LIGHT)-HVEM signaling axis, promoting Th1 and Tc1 polarization. The resulting IFNγ release triggers the differentiation of bone marrow-derived endothelial progenitor cells (EPC) into TA-HEVs. Furthermore, we show that Apelin (APLN), a multifunctional peptide hormone derived from both tumor and endothelial cells, plays a crucial role in driving the migration of EPC from the bone marrow and the spontaneous formation of TA-HEVs. Notably, we demonstrated that in the absence of therapies capable of modulating the immune response, TA-HEVs recruit naïve T cells into an immunosuppressive environment, potentially leading to their exhaustion. Our findings challenge the current paradigm that simply increasing TA-HEV formation will enhance anti-tumor immunity. They suggest that the quality of TA-HEVs and the surrounding microenvironment are critical determinants of their impact on anti-tumor immunity. These findings have significant implications for the development of novel therapeutic strategies for cancer, including targeting the pathways that regulate TA-HEV formation to improve the efficacy of immunotherapy.