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

ABSTRACT: The accessibility of cell surface proteins makes them tractable for cancer immunotherapy, but identifying suitable targets remains challenging, and resistance to treatment is common. Technical difficulties precluding the use of whole cell proteomic approaches to characterize cell surface proteins include low abundance, hydrophobicity, and a lack of protease cleavage sites. Furthermore, neither whole-cell proteomic nor transcriptomic data can accurately quantify protein expression at the plasma membrane. Resistance to immunotherapies is commonly mediated by downregulation of the target protein, a particular problem when immunotherapies fail to inhibit a specific biological pathway. Here we have used plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins and quantify for the first time the entire cell surface proteome of a primary cancer. This approach revealed a novel therapeutic target, SEMA4A, which we potently and selectively targeted with an antibody-drug conjugate in vitro and in vivo. Reduction of SEMA4A expression resulted in marked impairment of myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate SEMA4A to avoid detection. Our data therefore reveal not only a novel myeloma target but provide an exemplar of a top-down approach from the unbiased characterization of a cancer cell surface proteome to novel immunotherapeutic target.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Plasma Cell

DISEASE(S): Multiple Myeloma

SUBMITTER: James Williamson

LAB HEAD: Mike Chapman

PROVIDER: PXD014165 | Pride | 2022-01-24

REPOSITORIES: Pride

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

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