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

  • Nature. 2017 Sep 7;549(7670):101-105. doi: 10.1038/nature23643.
Marian L Burr  1  2  3 ,  Christina E Sparbier  1 ,  Yih-Chih Chan  1 ,  James C Williamson  3 ,  Katherine Woods  4  5 ,  Paul A Beavis  1  2 ,  Enid Y N Lam  1  2 ,  Melissa A Henderson  1  2 ,  Charles C Bell  1  2 ,  Sabine Stolzenburg  1 ,  Omer Gilan  1  2 ,  Stuart Bloor  3 ,  Tahereh Noori  1 ,  David W Morgens  6 ,  Michael C Bassik  6 ,  Paul J Neeson  1  2 ,  Andreas Behren  4  5 ,  Phillip K Darcy  1  2 ,  Sarah-Jane Dawson  1  2  7 ,  Ilia Voskoboinik  1  2 ,  Joseph A Trapani  1  2 ,  Jonathan Cebon  4  5 ,  Paul J Lehner  3 ,  Mark A Dawson  1  2  7  8
Affiliations
  • 1. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
  • 2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia.
  • 3. Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
  • 4. School of Cancer Medicine, La Trobe University, Melbourne, Victoria 3086, Australia.
  • 5. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia.
  • 6. Department of Genetics, Stanford University, Stanford, California, USA.
  • 7. Centre for Cancer Research, University of Melbourne, Melbourne, Australia.
  • 8. Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
PMID: 28813417 DOI: 10.1038/nature23643
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.