%0 Journal Article
%A Ho, Patricia
%A Melms, Johannes C
%A Rogava, Meri
%A Frangieh, Chris J
%A Poźniak, Joanna
%A Shah, Shivem B
%A Walsh, Zachary
%A Kyrysyuk, Oleksandr
%A Amin, Amit Dipak
%A Caprio, Lindsay
%A Fullerton, Benjamin T
%A Soni, Rajesh Kumar
%A Ager, Casey R
%A Biermann, Jana
%A Wang, Yiping
%A Khosravi-Maharlooei, Mohsen
%A Zanetti, Giorgia
%A Mu, Michael
%A Fatima, Hijab
%A Moore, Emily K
%A Vasan, Neil
%A Bakhoum, Samuel F
%A Reiner, Steven L
%A Bernatchez, Chantale
%A Sykes, Megan
%A Mace, Emily M
%A Wucherpfennig, Kai W
%A Schadendorf, Dirk
%A Bechter, Oliver
%A Shah, Parin
%A Schwartz, Gary K
%A Marine, Jean-Christophe
%A Izar, Benjamin
%T The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.
%J Cancer cell
%V 41
%N 7
%@ 1535-6108
%C New York, NY
%I Elsevier
%M DKFZ-2023-01194
%P 1207-1221.e12
%D 2023
%Z 2023 Jul 10;41(7):1207-1221.e12
%X The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
%K CD2 (Other)
%K CD58 (Other)
%K CRISPR-Cas9 screen (Other)
%K PDL1 (Other)
%K balance of co-inhibitory/co-stimulator (Other)
%K cancer immune evasion (Other)
%K cancer immunology (Other)
%K cancer immunotherapy (Other)
%K immune checkpoint blockade (Other)
%K mass spec screen (Other)
%K resistance to immune checkpoint blockade (Other)
%K single-cell RNA-sequencing (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37327789
%R 10.1016/j.ccell.2023.05.014
%U https://inrepo02.dkfz.de/record/276892