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.

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