LPL-Positive Endothelial Cells Control T-cell Homing in Liver Metastasis

Combination therapies involving vascular targeting drugs have shown promise in overcoming resistance to immunotherapy. However, the prerequisite for vascular modulation to evoke an effective antitumor T-cell response remains elusive. Tracing the transcriptional response of liver metastasis-associated peritumoral and tumor endothelial cells (TEC) to T-cell intervention, we discovered an immunomodulatory TEC subpopulation that highly expressed lipoprotein lipase (LPL). LPL+ TECs facilitated intratumoral homing of activated antitumor CD8+ T cells driving liver metastatic regression. Mechanistically, LPL enhanced MHC-I-dependent cross-presentation of tumor antigens on TECs for T-cell trafficking. Consequently, LPL+ TECs were recognized and targeted by T cells, further aiding antitumor response. Corresponding analyses of human liver metastasis samples identified a significant correlation between the presence of intratumoral LPL+ blood vessels and the accumulation of T cells. Altogether, the study identifies a decisive role of TECs in orchestrating an effective T-cell response by overcoming tumor's intrinsic insufficient antigen presentation. SIGNIFICANCE: The study identifies LPL+ TECs as orchestrators of activated CD8+ T-cell homing into immunologically cold tumors with low baseline MHC-I expression. Enhancing tumor antigen exposure by MHC-I cross-presentation in TECs presents a promising approach to compensate the intrinsic inability of tumor cells and boost antitumor immunotherapy.