CRISPR screen identifies that CMTM6 regulates the expression of PD-1L and anti-tumor immunity!

Nature. 2017 Aug 16. doi: 10.1038/nature23643. [Epub ahead of print]

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

Burr ML1,2,3, Sparbier CE1, Chan YC1, Williamson JC3, Woods K4,5, Beavis PA1,2, Lam EYN1,2, Henderson MA1,2, Bell CC1,2, Stolzenburg S1, Gilan O1,2, Bloor S3, Noori T1, Morgens DW6, Bassik MC6, Neeson PJ1,2, Behren A4,5, Darcy PK1,2, Dawson SJ1,2,7, Voskoboinik I1,2, Trapani JA1,2, Cebon J4,5, Lehner PJ3, Dawson MA1,2,7,8.

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.


Similar data was also published back to back by the Schumacher lab