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Mapping the Multiple Myeloma cell surface proteome for immune target discovery

ABSTRACT: Multiple myeloma (MM) is an incurable malignancy of plasma cells. Immunotherapy is a promising treatment option that relies on the identification of biologically and therapeutically relevant cell surface targets. We unbiasedly mapped the surfaceome of 7 MM cell lines and 904 primary MM patients bearing high-risk cytogenetics integrating Mass-Spectrometry and RNA-seq analyses. We developed an integrated database for cell surface molecule annotation and identified 326 candidates including immune-related proteins. By selecting the proteins with a favorable expression in normal tissues we validated 26 candidates in 30 primary relapsed/refractory MM patients and 11 targets resulted most highly and frequently expressed. We defined their protein abundance in normal hematopoietic stem cells and T-cells by flow-cytometry, narrowing the list to 6 top targets. By using the CRISPR/Cas9 system in MM cells, we found that knock-out (KO) of CCR1, LRRC8D and SEMA4A individually reduced cell growth in vitro and in vivo and blocked cell migration. Further, KO MM cells resulted more sensitive to treatment with Bortezomib or Venetoclax and increased T-cell proliferation when in co-culture with healthy T-cells compared to controls. Finally, by combining a CCR1 blocking antibody and SEMA4A and LRRC8D KO MM cell proliferation further decreased. This study provides a compelling target discovery pipeline that led to the identification and validation of novel immunotherapeutic targets with favorable expression in malignant and normal cells and highly likely playing critical functions in MM biology, suggesting potential novel immunotherapeutic approaches.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Perna Fabian

PROVIDER: MSV000088419 | MassIVE | Fri Nov 19 17:44:00 GMT 2021

REPOSITORIES: MassIVE

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Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

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Mapping the Multiple Myeloma cell surface proteome for immune target discovery

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