Tumor endothelial cells: gatekeepers and overlooked targets of anti-tumor immunity-implications for alternative immunotherapy?

 Immunotherapy (IT) is receiving increasing attention as a novel anticancer medicine, but suffers resistance in large fractions of cancer patients, also in lung cancer. Tumor immunity and endothelial cells (ECs) are intricately linked, as ECs express immune checkpoint proteins (ICP) and adhesion molecules on ECs facilitate immune cell trafficking. The best characterized ICP in cancer is programmed death ligand-1 (PD-L1), which is increased in murine tumor endothelial cells (TEC) in response to inflammation, but the contribution to anti-tumor immunity of PD-L1 is unclear. The host lab generated an atlas of lung TEC and normal ECs, using single cell RNA-sequencing, uncovering: (i) TEC subpopulations with an interferon-regulated gene signature, showing high expression of PD-L1; (ii) TECs with antigen-presentation capacity; and (iii) high endothelial venule-like TECs, facilitating immune cell infiltration. I will characterize the contribution of PD-L1+ TECs to anti-tumor immunity by studying tumor development and immunity in EC specific conditional PD-L1 knock-out mice. Moreover, I will identify novel TEC-immune cell interactions in silico using predictive software to analyze single cell interactomes and in situ using spatial transcriptomics on lung tumor sections. Besides unprecedented insights into the contribution of PD-L1+ TECs to tumor immunity, this study pioneers the identification of TEC-immune cell interactions to generate novel putative targets to improve or develop IT