Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma

The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins of a pri...

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Bibliographic Details
Published in:Blood 2022-04, Vol.139 (16), p.2471-2482
Main Authors: Anderson, Georgina S.F., Ballester-Beltran, Jose, Giotopoulos, George, Guerrero, Jose A., Surget, Sylvanie, Williamson, James C., So, Tsz, Bloxham, David, Aubareda, Anna, Asby, Ryan, Walker, Ieuan, Jenkinson, Lesley, Soilleux, Elizabeth J., Roy, James P., Teodósio, Ana, Ficken, Catherine, Officer-Jones, Leah, Nasser, Sara, Skerget, Sheri, Keats, Jonathan J., Greaves, Peter, Tai, Yu-Tzu, Anderson, Kenneth C., MacFarlane, Marion, Thaventhiran, James E., Huntly, Brian J.P., Lehner, Paul J., Chapman, Michael A.
Format: Article
Language:English
Subjects:
Cell Membrane - metabolism
Humans
Immunobiology and Immunotherapy
Immunologic Factors
Immunotherapy
Membrane Proteins
Multiple Myeloma - genetics
Multiple Myeloma - therapy
Proteomics
Semaphorins - genetics
Semaphorins - metabolism
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Summary:The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins of a primary cancer. We used a novel approach to prioritize immunotherapy targets and identified a cell surface protein not previously implicated in myeloma, semaphorin-4A (SEMA4A). Using knock-down by short-hairpin RNA and CRISPR/nuclease-dead Cas9 (dCas9), we show that expression of SEMA4A is essential for normal myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate the protein to avoid detection. We further show that SEMA4A would not be identified as a myeloma therapeutic target by standard CRISPR/Cas9 knockout screens because of exon skipping. Finally, we potently and selectively targeted SEMA4A with a novel antibody–drug conjugate in vitro and in vivo. •Quantification of the primary myeloma cell surface proteome enables unbiased discovery of novel therapeutic targets.•Targeting SEMA4A using an antibody–drug conjugate potently and selectively eradicates myeloma cells both in vitro and in vivo. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2021015161