TY  - JOUR
A1  - Zhuang, Xiaoxuan
A1  - Woods, James
A1  - Ji, Yanlong
A1  - Scheich, Sebastian
A1  - Mo, Fei
A1  - Rajagopalan, Sumati
A1  - Coulibaly, Zana A.
A1  - Voss, Matthias
A1  - Urlaub, Henning
A1  - Staudt, Louis M.
A1  - Pan, Kuan-Ting
A1  - Long, Eric O.
T1  - Functional genomics identifies N-acetyllactosamine extension of complex N-glycans as a mechanism to evade lysis by natural killer cells
T2  - Cell Reports
N2  - Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
KW  - cancer
KW  - immunotherapy
KW  - natural killer
KW  - NK cell
KW  - B cell cancer
KW  - SPPL3
KW  - N-glycosylation
KW  - poly-LacNAc
KW  - glycosyltransferase
KW  - B3GNT2
KW  - CRISPR screen
KW  - rituximab
Y1  - 2024
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/83751
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-837516
SN  - 2211-1247
VL  - 43
IS  - 4, art. 114105
SP  - 1
EP  - 22
PB  - Elsevier
CY  - Amsterdam
ER  -