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BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions
Fumou Sun, … , John D. Shaughnessy Jr., Fenghuang Zhan
Fumou Sun, … , John D. Shaughnessy Jr., Fenghuang Zhan
Published October 26, 2023
Citation Information: J Clin Invest. 2024;134(1):e171396. https://doi.org/10.1172/JCI171396.
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Research Article Hematology Oncology Article has an altmetric score of 7

BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions

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Abstract

We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase–positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA–CAR-T and BCMA–CST6–CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro–computed tomography images revealed that BCMA–CST6–CAR-T cells, but not BCMA–CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.

Authors

Fumou Sun, Yan Cheng, Jin-Ran Chen, Visanu Wanchai, David E. Mery, Hongwei Xu, Dongzheng Gai, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Frits van Rhee, Guido Tricot, John D. Shaughnessy Jr., Fenghuang Zhan

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Figure 4

BCMA–CST6–CAR-T cells suppress osteoclast differentiation.

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BCMA–CST6–CAR-T cells suppress osteoclast differentiation.
(A) Experimen...
(A) Experimental workflow for the detection of TRAP+ osteoclasts. (B) CST6 concentrations in supernatants were detected at E/T ratios of 1:5 to 5:1 after 24 hours of coculturing (n = 5). (C) CAR-T cells were incubated with MM1.S cells at ratios of 1:5 to 5:1 for 24 hours, and CM were collected and added into RAW 264.7 cells with RANKL. On day 7, osteoclasts were stained with TRAP solution (n = 5, representative result from 5 independent experiments). Scale bars: 200 μm. (D) Bar plots present quantifications of the TRAP+ area (n = 5). (E) Human CD14+ monocytes sorted from bone marrow of patients with MM were differentiated into osteoclasts with M-CSF and RANKL for 7 days. CM were added to human CD14+ monocyte culture media (50%) for another 7 days. On day 14, osteoclasts were stained with TRAP solution (n = 5, representative result from 5 independent experiments). Scale bars: 200 μm. (F) Bar plots represent the number of TRAP+ osteoclasts derived from human CD14+ monocytes per view (n = 5). Data represent the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA; NS = P > 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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