Defining the cell surface proteomic landscape of multiple myeloma reveals immunotherapeutic strategies and biomarkers of drug resistance

• Published in: bioRxiv
• Main Authors: Ferguson, Ian D, Bonell Patiño Escobar, Tuomivaara, Sami T, Lin, Yu-Hsiu T, Nix, Matthew A, Leung, Kevin K, Hale, Martina, Choudhry, Priya, Lopez-Girona, Antonia, Ramos, Emilio, Wong, Sandy W, Wolf, Jeffrey L, Martin, Thomas G, Shah, Nina, Vandenberg, Scott, Prakash, Sonam, Besse, Lenka, Driessen, Christoph, Wells, James A, Wiita, Arun P
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.01.2021
• Subjects: Avidity; Biomarkers; Cell culture; Cell surface; Drug resistance; Gene expression; Intelligence; Lymphocytes B; Malignancy; Microenvironments; Multiple myeloma; Plasma cells; Proteasome inhibitors; Proteomes; Proteomics; Research funding; Stockholders; Surface markers; Transcriptomes
• DOI: 10.1101/2021.01.17.427038

ABSTRACT The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to both proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary myeloma patient plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma. Competing Interest Statement A.P.W. is a member of the Scientific Advisory Board and holds equity stakes in Indapta Therapeutics and Protocol Intelligence, LLC. J.A.W. is on the Scientific Advisory Board and holds equity stakes in the following companies with oncology interests: Soteria Biotherapeutics, Jnana Therapeutics, Inception Therapeutics, and Inzen Therapeutics, and holds a sponsored research agreement with Bristol Myers Squibb. S.W.W. has received research funding from Janssen, GlaxoSmithKline, Bristol Myers Squibb, Genentech, and Fortis, and served as a consultant to Amgen. T.G.M. has received research funding from Sanofi, Janssen, and Amgen and has served as a consultant to GlaxoSmithKline. A. L.-G. is an employee and shareholder of Celgene/Bristol Myers Squibb. P.C. is currently an employee and shareholder of Roche/Genentech but was solely employed by UCSF during her participation on this project. The other authors declare no relevant conflicts of interest.