CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
Article on the regulation of PD-L1
- Marian L. Burr, Christina E. Sparbier, Yih-Chih Chan, James C. Williamson,Katherine Woods, Paul A. Beavis, Enid Y. N. Lam, Melissa A. Henderson, Charles C. Bell, Sabine Stolzenburg, Omer Gilan, Stuart Bloor, Tahereh Noori, David W. Morgens, Michael C. Bassik, Paul J. Neeson, Andreas Behren, Phillip K. Darcy, Sarah-Jane Dawson, Ilia Voskoboinik, Joseph A. Trapani, Jonathan Cebon, Paul J. Lehner, & Mark A. Dawson
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance1, 2. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression1. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR–Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, we find that CMTM6 displays specificity for PD-L1. Notably, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo. These findings provide insights into the biology of PD-L1 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a potential therapeutic target to overcome immune evasion by tumour cells.
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