The tumor endothelium: an overlooked target to improve immunotherapy?

Immunotherapy (IT) is a highly promising anti-cancer therapy but is plagued by resistance caused by insufficient recruitment of immune cells to the tumor stroma and by tolerance. To improve IT, we will explore the immunosuppressive behavior of the tumor endothelium and tune tumor endothelial cells (TECs, lining the tumor vasculature) to become phenotypically immunocompetent and to allow for improved T cell recruitment into the tumor stroma. First, we will assess the incompletely understood role of the TEC-expressed (versus cancer cell-expressed) immune checkpoint inhibitor PDL1 in dampening T cell activation, both in vitro and in mice lacking PDL1 in the endothelium. Second, we observed in our single cell RNA-seq analysis on human lung cancer TECs that a substantial fraction of TECs are fully geared to act as antigen presenting cells (APCs) but lack the co-activators CD80/CD86. We will tune these TECs from semi-professional to professional APCs by overexpression of CD80/CD86 and assess the impact on tumor growth and IT efficiency. Third, we found that another subset of TECs displayed a transcriptome signature of high-endothelial-venules (HEVs), involved in immune T cell recruitment. We will explore if promotion of HEV biogenesis in TECs via overexpression of a combinatorial code of transcription factors improves IT. Finally, we will translate our findings, by exploring the use of a novel TEC delivery method to tune TECs into professional APCs and HEVs.