The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance

Ferguson, Ian; Patiño-Escobar, Bonell; Tuomivaara, Sami T.; Lin, Yu-Hsiu T.; Nix, Matthew A.; Leung, Kevin; Kasap, Corynn; Ramos, Emilio; Vasquez, Wilson Nieves; Talbot, Alexis; Hale, Martina; Naik, Akul; Kishishita, Audrey; Choudhry, Priya; López-Girona, Antonia; Miao, Weili; Wong, Sandy W.; Wolf, Jeffrey L.; Martin, Thomas G.; Shah, Nina; Vandenberg, Scott; Prakash, Sonam; Besse, Lenka; Posey, Avery D.; Mullins, R. Dyche; Eyquem, Justin; Wells, James A.; Wiita, Arun P.

doi:10.1038/s41467-022-31810-6

Cited by 50 publications

(47 citation statements)

References 70 publications

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“…1d and Supplementary Dataset 2 ). While enrichment for membrane-spanning proteins for PhoX was less than DSSO, at 27.9 %, this value was still broadly consistent with our prior studies using CSC alone 7 . Combining DSSO and PhoX data, our “structural surfaceomics” approach identified 2,390 total inter-linked and intra-linked peptides on Nomo-1 cells.…”

Section: Resultssupporting

confidence: 90%

“…The copyright holder for this preprint this version posted October 11, 2022. ; https://doi.org/10.1101/2022.10.10.511511 doi: bioRxiv preprint using CSC alone 7 . Combining DSSO and PhoX data, our "structural surfaceomics" approach identified 2,390 total inter-linked and intra-linked peptides on Nomo-1 cells.…”

Section: Development and Application Of The Structural Surfaceomics T...mentioning

confidence: 99%

“…Recently, we were intrigued by the discovery of an activated conformation of integrin-β7 as a specific cellular therapy in multiple myeloma 5 . In commonly-used target discovery pipelines, relying entirely on analysis of transcript and/or protein expression levels 6 , integrin-β7 would not be considered an optimal target due to widespread expression on other hematopoietic cells 7 . However, oncogenic signaling was proposed to drive the aberrant constitutive activation of this integrin on myeloma 8, 9 .…”

Section: Introductionmentioning

confidence: 99%

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Structural surfaceomics reveals an AML-specific conformation of Integrin-β2 as a CAR-T therapy target

Mandal

Wicaksono

et al. 2022

Preprint

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Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here, we explore the hypothesis that tumor cells express cancer-specific surface protein conformations, invisible to standard target discovery pipelines evaluating gene or protein expression, that can be identified and immunotherapeutically targeted. We term this strategy, integrating cross-linking mass spectrometry (XL-MS) with glycoprotein surface capture- structural surfaceomics. As a proof of principle, we apply this technology to acute myeloid leukemia, a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin-β2 as a structurally-defined, widely-expressed, AML-specific target. We develop and characterize recombinant antibodies to this protein conformation, and show that chimeric antigen receptor (CAR) T-cells eliminate AML cells and patient-derived xenografts without notable toxicity versus normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen while demonstrating a toolkit for applying these strategies more broadly.

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Section: Resultssupporting

confidence: 90%

Section: Development and Application Of The Structural Surfaceomics T...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural surfaceomics reveals an AML-specific conformation of Integrin-β2 as a CAR-T therapy target

Mandal

Wicaksono

et al. 2022

Preprint

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“…1b ). MM patients with high levels of SLC3A2 or SLC7A5 protein expression by immunohistological staining had inferior progression-free survival 25 , and a recent study found that SLC3A2 and SLC7A5 were among the most abundant proteins on the surface of MM cells 50 . SLC3A2 may have a prominent role in plasma cells because these cells fundamentally serve as protein production factories, secreting large quantities of antibodies that require vast reserves of amino acids 51 , 52 .…”

Section: Discussionmentioning

confidence: 99%

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

et al. 2022

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Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this mode of RAS signaling.

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“…Multiple myeloma (MM), as a malignant proliferative disease of bone marrow plasma cells, belongs to the category of B cell lymphoma, characterized by abnormal proliferation of plasma cells with the overproduction of monoclonal immunoglobulin or light chain (M protein) [ 1 , 2 ], with no effective healing method at present. Patients still have a high possibility of recurrence after complete remission [ 3 , 4 ], so that the system of recurrence prediction is very important in the prevention and treatment of MM.…”

Section: Introductionmentioning

confidence: 99%

Predictive Value Analysis of Serum Ig A, Ig G, and TNF-α in Recurrence of Multiple Myeloma

2022

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Objective. The study is aimed at analyzing the predictive value of serum Ig A, Ig G, and TNF-α in the recurrence of multiple myeloma (MM). Methods. 136 patients with MM treated in our hospital from January 2010 to January 2017 were followed up for 5 years. Finally, 100 patients who met the inclusion and exclusion criteria and had the complete follow-up visit were selected as the study subjects, with the recurrence of MM as endpoint event, and the observation was taken until the occurrence of endpoint event in patients or the termination of this study. They were divided into the recurrence group (RG) and the nonrecurrence group (NRG) according to whether the endpoint event occurred. The venous blood of patients was collected at the first diagnosis and subsequent visit (at the time of recurrence or termination of the study) to measure the Ig A and Ig G using a full automatic special protein analyzer and the TNF-α level by enzyme-linked immunosorbent assay. The data obtained in this study were analyzed by univariate analysis to choose the factors with difference in statistical significance to draw the ROC curve, and the areas under the curve (AUC) were recorded to analyze the potential mechanism of Ig A, Ig G, and TNF-α in predicting the recurrence of MM. Results. After follow-up visit, there were 62 patients with recurrence (62.0%) and 38 patients without recurrence (38.0%), with no obvious difference in gender, age, body weight, and immune classification between the two groups ( P > 0.05 ). Compared with the NRG, the levels of soluble interleukin-2 receptor (sIL-2R) and β2-microglobulin (β2-MG) in the RG at the first diagnosis were distinctly higher ( P < 0.001 ); the levels of Ig A, Ig G, and TNF-α in the RG at the first diagnosis were visibly higher ( P < 0.05 ); and the levels of Ig A, Ig G, and TNF-α in the RG at the subsequent visit were clearly higher ( P < 0.05 ). There was a correlation between Ig G, Ig A, and TNF-α and β2-MG at the first diagnosis and the subsequent visit ( P < 0.05 ); there was a correlation between Ig G and TNF-α, and sIL-2R at the first diagnosis and the subsequent visit ( P < 0.05 ); and there was a correlation between Ig A and sIL-2R at the subsequent visit ( P < 0.05 ). The AUC of Ig G, Ig A, and TNF-α in predicting the MM at the first diagnosis were 0.772, 0.776, and 0.778, respectively. Conclusion. The serum Ig A, Ig G, and TNF-α had a predictive value in the recurrence of MM, and TNF-α was correlated with sIL-2R and β2-MG, with the highest AUC and the best predictive value.

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The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance

Cited by 50 publications

References 70 publications

Structural surfaceomics reveals an AML-specific conformation of Integrin-β2 as a CAR-T therapy target

Structural surfaceomics reveals an AML-specific conformation of Integrin-β2 as a CAR-T therapy target

Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Predictive Value Analysis of Serum Ig A, Ig G, and TNF-α in Recurrence of Multiple Myeloma

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