Tumor endothelial cells: gatekeepers of anti-tumor immunity
Immunotherapy, in the form of immune checkpoint inhibitors, is the upcoming anti-cancer therapy, but suffers resistance in large fractions of cancer patients (also lung cancer). Tumors stimulate angiogenesis to ensure their supply of nutrients, however much less studied is how tumor endothelial cells (TECs) contribute to immunosuppression. Endothelial cells (ECs) represent a major non-hematopoietic component of immunity and TECs are presumed to be immunosuppressive, in part by expressing elevated levels of PD-L1. However, the role and dynamics of TEC-expressed PD-L1 in anti-tumor immunity relative to the cancer expressed PD-L1 remain incompletely understood.

Given the strategic “1st line” location of TECs, the question raises if at least part of the success of PD-L1 inhibition, is attributable to an effect on TEC immunity. Therefore, for the 1st time, I will fill this gap of knowledge by characterizing mice lacking PD-L1 in ECs and assess tumor progression and anti-tumor immunity in these mice using different tumor models. I will assess the efficacy of anti-PD-L1 blockade in mice lacking PD-L1 in ECs in different stages of tumor growth to delineate the dynamics of PD-L1 expression in TECs. Moreover, by using established in vitro approaches, I will study the effect of PD-L1 knock-down in human lung tumor derived TECs vs. normal ECs on human T cell proliferation, effector function and transmigration. The proposed research provides unprecedented insights in the relative role of tumor endothelial vs. cancer cell-derived PD-L1 in immunosuppression.

This is a multi-disciplinary project at the interface of angiogenesis, immunology and cancer. Combining my expertise on T cell biology with the host’s expertise in angiogenesis and exceptional scientific infrastructure (core facilities) and innovative science (EC:T cell interactions during immunotherapy) will ensure successful achievement of the project goals and provide a highly competitive training for my future career.