ECONOMY · Endothelial Cells - an Overlooked Non-hematopoietic cOmponent of tuMor immunitY

Despite decades of research, cancer remains the second leading cause of death globally. Amongst all cancers, lung cancer is the deadliest in both men and women worldwide. Immune checkpoint blockade (ICB) recently emerged as promising cancer therapy. While extremely successful in hematopoietic cancers and melanoma, success in lung cancer is very limited. We are therefore in desperate need to devise novel treatment strategies. One approach would involve remodelling the lung cancer immune landscape to improve clinical response to ICB. A so far overlooked non-hematopoietic component of the immune system which potentially greatly contribute to tumor immunity are endothelial cells (ECs). Most intriguingly, tumor EC (TEC) subsets expressing diverse immune markers were identified, in parallel with the discovery of diverse metabolic phenotypes in TECs. The host lab identified TECs with transcriptional signatures related to antigen processing and presentation (MHCII+). However, the functional significance of MHCII+ TECs in tumor immunity and whether their immune-related functions could be regulated by underlying metabolic programming is unknown. Given the strategic ""first line"" location of TECs in the tissue, the question is whether, ICB’s effectiveness can be partly attributed to TEC immunity. I therefore propose to investigate the interactions between MHCII+ TECs and T cells and the effects of such interactions on tumor immunity using state-of-the-art inducible EC-specific MHCII knock-out mice. Moreover, I will assess metabolic signatures in immune-TECs and test potential metabolic regulation of TECs’ immune functions. Such metabolism-driven regulation could open new therapeutic possibilities, utilizing already available pharmaceutical inhibitors to remodel the tumor immune landscape in order to create a favourable context for immunotherapy. Thus, the proposed research is expected to pave the way for exciting new combination treatment strategies for lung cancer.""