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

CMTM6 maintains PD-L1 at the plasma membrane by inhibiting its lysosome-mediated degradation and promoting its recycling. Understanding the molecular regulation of programmed death-1 ligand 1 (PD-L1) expression could help to explain the success of certain anti-tumour therapies that disrupt PD-L1-mediated tumour tolerance. Mark Dawson and colleagues identify a novel regulator of PD-L1 expression, CMTM6, through a genome-wide CRISPR–Cas9 screen. CMTM6 functions to maintain PD-L1 at the plasma membrane by inhibiting its lysosome-mediated degradation and promoting its recycling. Elsewhere in this issue, Ton Schumacher and colleagues describe a haploid genetic screen to identify molecules and pathways that influence the cell surface expression of PD-L1. They also identify chemokine-like factors CMTM6 and CMTM4 as cell endogenous regulators of PD-L1 stability, and suggest that this axis could be targeted therapeutically to improve cancer immunotherapy. 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.