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 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.M.L.B. is supported by a Cancer Research UK Clinician Scientist Fellowship (C53779/A20097), Addenbrooke’s Charitable Trust award and NIHR fellowship.
P.J.L. is supported by a Wellcome Trust PRF (101835/Z/13/Z) and work in the Lehner laboratory is supported by NHSBT, NIHR Cambridge BRC, a Wellcome Trust Strategic Award to CIMR, and the Addenbrooke’s Charitable Trust
M.A.D. is supported by a Senior Leukaemia Foundation Australia Fellowship and work in the Dawson laboratory is supported by the NHMRC (Grants 1085015, 1106444 and 1106447) Cancer Council Victoria and Leukaemia Foundation Australia. Cancer Research UK (C53779/A20097
