Grant: Project Grant

Important hallmarks of cancer are the ability of tumour cells to evade rejection by the immune system, ability to spread, and resistance to therapy. One way tumour cells avoid immune rejection is by inactivating immune cells through the interaction of specific cell surface molecules, a mechanism referred to as "immune checkpoint". One of these immune checkpoints involves the interaction of a molecule on immune cells, the Programmed Death 1 (PD-1) with another molecule, the Programmed Death Ligand 1 ligand (PD-L1), on tumour cells. This interaction results in the inactivation of immune cells that would otherwise kill the tumour cells. Thus, exciting new therapeutic approaches are designed to interfere with the PD-1/PD-L1 immune checkpoint in order to control cancer. Some of these approaches have shown unprecedented and highly encouraging clinical responses in patients with various advanced cancers. We have evidence that, independently of its effects on immune cell inactivation, interaction of PD-1 with PD-L1 also promotes malignant properties (drug resistance and invasiveness) in the tumour cells. Hence, this immune checkpoint has a dual effect: it inactivates anti-tumour immune responses and endows tumour cells with aggressive properties. We plan to test the hypothesis that PD-1/PD-L1 signalling in tumour cells contributes to metastatic ability and resistance to chemotherapy. We will conduct studies that will lead us to an understanding of the mechanism by which PD-1/PD-L1 leads to aggressive properties in tumour cells. We plan to accomplish this using animal and cell culture models in which we will manipulate (stimulate or block) the PD-1/PD-L1 immune checkpoint and determine how such manipulation affects metastatic ability and drug resistance. These studies are important because they could help us improve therapies designed to target the PD-1/PD-L1 immune checkpoint.