Using a genome-wide CRISPR-Cas9 screen, Burr et al. identified the ubiquitously expressed protein CMTM6 as a critical regulator of PD-L1. CMTM6 co-localizes with PD-L1 at the plasma membrane and maintains PD-L1 cell surface expression by preventing PD-L1 from being targeted for lysosome-mediated degradation during endocytic recycling. Both human in vitro and murine in vivo results support consideration of CMTM6 as a novel immunotherapeutic target.
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.
Author Info: (1) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052
Author Info: (1) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. (2) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. (3) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. (4) Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. (5) School of Cancer Medicine, La Trobe University, Melbourne, Victoria 3086, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia. (6) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (7) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (8) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (9) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (10) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. (11) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (12) Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. (13) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. (14) Department of Genetics, Stanford University, Stanford, California, USA. (15) Department of Genetics, Stanford University, Stanford, California, USA. (16) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (17) School of Cancer Medicine, La Trobe University, Melbourne, Victoria 3086, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia. (18) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (19) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. Centre for Cancer Research, University of Melbourne, Melbourne, Australia. (20) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (21) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. (22) School of Cancer Medicine, La Trobe University, Melbourne, Victoria 3086, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia. (23) Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. (24) Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia. Centre for Cancer Research, University of Melbourne, Melbourne, Australia. Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
