Investigating the role of CMTM proteins in the regulation of PD-L1 expression

The interaction between programmed cell death protein 1 (PD-1) receptor, expressed on activated T cells, andits ligand programmed death-ligand 1 (PD-L1), expressed mostly but not only on tumor cells, is a major mechanism inhibiting T cell activities. The expression of high levels of PD-L1 by various cancers leads to tumor escape from T cell immunity. Despite the remarkable clinical outcome achieved using immune checkpoint inhibitors to block PD-L1/PD-1 interaction, the response rates remain limited in several solid tumors.
Aggressive tumor cells succeed to continuously upregulate the expression of PD-L1. Therefore, fostering our understanding of the regulatory mechanisms of PD-L1 expression will improve the efficacy of current PD-L1/PD-1 blockade and provide substantial benefits to cancer patients. Two interconnected processes havebeen described to upregulate the expression of PD-L1 and other immune checkpoints: The Epithelial Mesenchymal transition (EMT) and hypoxic tumor microenvironment. We provided experimental evidence showing that EMT and hypoxia, through SNAI1 and HIF-1, respectively, increase PD-L1 surface expression by upregulating two new players: The CMTM6 and CMTM7 proteins. We showed that, collectively, CMTM6 and CMTM7 proteins regulate the expression of a significant part of surface PD-L1 on tumor cells undergoing EMT. This project is designed to provide mechanistic insights into how SNAI1 and HIF-1 regulate CMTM6 and CMTM7 expression in the context of EMT and hypoxia, and the impact of EMT- and hypoxia-dependent CMTM6 and CMTM7 upregulation on T cell functions. The project also relies on validating the concept that targeting CMTM6/7 would improve the therapeutic benefit of anti-PD-1 immunotherapy. This project will pave the way for the development of innovative strategies modulating CMTM6/7 expression to alleviate the immune suppression in tumors highly addicted to the EMT and hypoxia.