PD-1/PD-L1 pathway: Deciphering the PD-1-binding capacity of tumor cells-PD-L1

Details

Supervisors

Van Den Eynde, Benoît ; Zhu, Jingjing

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

PD-1/PD-L1 interaction blockade is one of the main breakthroughs in cancer immunotherapy since it dramatically and sustainably increases patients’ overall survival. However, there is still a large majority of patients who do not benefit from these treatments, mainly because of immunosuppressive mechanisms occurring in the tumor microenvironment, leading to tumor immune evasion. The acquired knowledge gained over the past 2 decades regarding the PD-1/PD-L1 pathway are constantly being challenged by the new findings that are gradually emerging in the field of immunology. An in-depth analysis of PD-L1 and its biological basis demonstrated that its immunosuppressive effects in the tumor microenvironment cannot be attributed solely to its expression on the surface of tumor cells, and that the role of PD-L1-expressing immune cells is often overlooked. Recent papers described that the ligation of PD-L1 with PD-1 is not a systematic occurring event, and that its interaction with CD80 on the surface of antigen-presenting cells prevents its interaction with PD-1 on T-cells. Previous observations in the host lab led to a similar statement regarding PD-1/PD-L1 binding on tumor cells which do not express CD80, indicating that CD80 cannot be held solely responsible for the lack of PD-1/PD-L1 interaction on the cell surface. In order to identify other proteins that could be responsible for the lack of PD-1/PD-L1 interaction, we performed a co-immunoprecipitation of PD-L1 and its interacting proteins. The elution product was analyzed by mass spectrometry, and a computational analysis allowed us to identify that EphA2, another membrane protein, was the most convincing candidate to interact with PD-L1. Unfortunately, the knock-out experiments of EphA2 did not allow us to rescue the binding of PD-1. Despite this, we were able to confirm, by co-immunoprecipitation, that these two proteins interacted, suggesting a more in-depth study of the modalities of this interaction.