TY  - JOUR
AU  - Ho, Patricia
AU  - Melms, Johannes C
AU  - Rogava, Meri
AU  - Frangieh, Chris J
AU  - Poźniak, Joanna
AU  - Shah, Shivem B
AU  - Walsh, Zachary
AU  - Kyrysyuk, Oleksandr
AU  - Amin, Amit Dipak
AU  - Caprio, Lindsay
AU  - Fullerton, Benjamin T
AU  - Soni, Rajesh Kumar
AU  - Ager, Casey R
AU  - Biermann, Jana
AU  - Wang, Yiping
AU  - Khosravi-Maharlooei, Mohsen
AU  - Zanetti, Giorgia
AU  - Mu, Michael
AU  - Fatima, Hijab
AU  - Moore, Emily K
AU  - Vasan, Neil
AU  - Bakhoum, Samuel F
AU  - Reiner, Steven L
AU  - Bernatchez, Chantale
AU  - Sykes, Megan
AU  - Mace, Emily M
AU  - Wucherpfennig, Kai W
AU  - Schadendorf, Dirk
AU  - Bechter, Oliver
AU  - Shah, Parin
AU  - Schwartz, Gary K
AU  - Marine, Jean-Christophe
AU  - Izar, Benjamin
TI  - The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.
JO  - Cancer cell
VL  - 41
IS  - 7
SN  - 1535-6108
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2023-01194
SP  - 1207-1221.e12
PY  - 2023
N1  - 2023 Jul 10;41(7):1207-1221.e12
AB  - 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.
KW  - CD2 (Other)
KW  - CD58 (Other)
KW  - CRISPR-Cas9 screen (Other)
KW  - PDL1 (Other)
KW  - balance of co-inhibitory/co-stimulator (Other)
KW  - cancer immune evasion (Other)
KW  - cancer immunology (Other)
KW  - cancer immunotherapy (Other)
KW  - immune checkpoint blockade (Other)
KW  - mass spec screen (Other)
KW  - resistance to immune checkpoint blockade (Other)
KW  - single-cell RNA-sequencing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37327789
DO  - DOI:10.1016/j.ccell.2023.05.014
UR  - https://inrepo02.dkfz.de/record/276892
ER  -