CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity.

2017

Burr, Marian L

Sparbier, Christina E

Chan, Yih-Chih

Williamson, James C

Woods, Katherine

Beavis, Paul A

Lam, Enid Y N

Henderson, Melissa A

Bell, Charles C

Stolzenburg, Sabine

Gilan, Omer

Bloor, Stuart

Noori, Tahereh

Morgens, David W

Bassik, Michael C

Neeson, Paul J

Behren, Andreas

Darcy, Phillip K

Dawson, Sarah-Jane

Voskoboinik, Ilia

Trapani, Joseph A

Cebon, Jonathan S

Lehner, Paul J

Dawson, Mark A

Journal Article

10.1038/nature23643

Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. 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.

link

Nature 2017; 549(7670): 101-105

Nature