CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
Marian L. Burr,Marian L. Burr,Marian L. Burr,Christina E. Sparbier,Yih-Chih Chan,James C Williamson,Katherine Woods,Paul A. Beavis,Paul A. Beavis,Enid Y.N. Lam,Enid Y.N. Lam,Melissa A. Henderson,Melissa A. Henderson,Charles C. Bell,Charles C. Bell,Sabine Stolzenburg,Omer Gilan,Omer Gilan,Stuart Bloor,Tahereh Noori,David W. Morgens,Michael C. Bassik,Paul J Neeson,Paul J Neeson,Andreas Behren,Phillip K. Darcy,Phillip K. Darcy,Sarah-Jane Dawson,Sarah-Jane Dawson,Ilia Voskoboinik,Ilia Voskoboinik,Joseph A. Trapani,Joseph A. Trapani,Jonathan Cebon,Paul J. Lehner,Mark A. Dawson +35 more
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TLDR
Insight is provided into the biology of PD-L1 regulation, a previously unrecognized master regulator of this critical immune checkpoint is identified, and a potential therapeutic target to overcome immune evasion by tumour cells is highlighted.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.read more
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Regulation and Function of the PD-L1 Checkpoint
TL;DR: The roles of the PD-1-PD-L1 axis in cancer is reviewed, focusing on recent findings on the mechanisms that regulate PD-L 1 expression at the transcriptional, posttranscriptional, and protein level, to inform the design of more precise and effective cancer immune checkpoint therapies.
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Mauro Poggio,Tianyi Hu,Chien Chun Pai,Brandon Chu,Cassandra D. Belair,Anthony Chang,Elizabeth Montabana,Ursula E. Lang,Qi Fu,Lawrence Fong,Robert Blelloch +10 more
TL;DR: The findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches, and is described as a potential new therapeutic target for cancer patients.
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Dongqiang Zeng,Meiyi Li,Rui Zhou,Jingwen Zhang,Huiying Sun,Min Shi,Jianping Bin,Yulin Liao,Jinjun Rao,Wangjun Liao +9 more
TL;DR: Depicting a comprehensive landscape of the TME characteristics of Gastric cancer may help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.
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