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

Anderson, Georgina S. F.; Guerrero López, José Antonio; et al.

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

dc.contributor.author	Anderson, Georgina S. F.
dc.contributor.author	Guerrero López, José Antonio
dc.contributor.author	et al.
dc.contributor.department	Medicina Interna
dc.date.accessioned	2026-02-03T08:58:38Z
dc.date.available	2026-02-03T08:58:38Z
dc.date.copyright	© 2022 by The American Society of Hematology
dc.date.issued	2022-04-21
dc.description.abstract	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.
dc.format	application/pdf
dc.format.extent	12
dc.identifier.citation	Blood® 21 April 2022 \| vol. 139, Nº 16
dc.identifier.doi	https://doi.org/10.1182/blood.2021015161
dc.identifier.eissn	1528-0020
dc.identifier.issn	0006-4971
dc.identifier.uri	http://hdl.handle.net/10201/198529
dc.language	eng
dc.publisher	American Society of Hematology (ASH Publications)
dc.relation	This research was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215- 20014). G.S.F.A. was supported by a Cancer Research UK (CRUK) studentship (C48525/A18347) and by the MRC Toxicology Unit (MC_UU_00025/10). Work in the laboratory of B.J.P.H. was supported by a CRUK program grant (C18680/A25508), a European Research Council Consolidator award (COMAL 647685), and the NIHR Cambridge Biomedical Research Centre. Work in the laboratory of P.J.L. was supported by a Wellcome Trust Principal Research Fellowship (210688/Z/18/Z). Work in the laboratory of M.M. was funded by the MRC Toxicology Unit (MC_UU_00025/4). Work in the laboratory of J.E.T. was funded by the MRC Toxicology Unit (MC_UU_0025/12). Work in the laboratory of M.A.C. was funded by a Wellcome-Beit Intermediate Fellowship (098638/Z/12/Z), a Multiple Myeloma Research Foundation Senior Research Grant, a CRUK Biotherapeutic Drug Discovery Project Award (A24724), and by the MRC Toxicology Unit (MC_UU_00025/10).
dc.rights	Attribution-NonCommercial-NoDerivatives 4.0 International	*
dc.rights.accessRights	info:eu-repo/semantics/openAccess
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	*
dc.subject.ods	Objetivo 3: Salud
dc.title	Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/publishedVersion
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