CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity Academic Article uri icon

abstract

  • 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.

authors

  • Burr, Marian L
  • Sparbier, Christina E
  • Chan, Yih-Chih
  • Williamson, James C
  • Woods, Katherine
  • Beavis, Paul A
  • Lam, Enid YN
  • 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
  • Lehner, Paul J
  • Dawson, Mark A

publication date

  • 2017

published in