Reconstitution of the Multiple Myeloma Microenvironment Following Lymphodepletion with BCMA CAR-T Therapy

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2024 Jul 18

PMID 39024031

Authors

Yazi Yang

Sen Qin

Mengyu Yang

Ting Wang

Ru Feng

Chunli Zhang

Enrun Zheng

Qinghua Li

Pengyu Xiang

Shangyong Ning

Xiaodong Xu

Xin Zuo

Shuai Zhang

Xiaoya Yun

Xuehong Zhou

Yue Wang

Lin He

Yongfeng Shang

Luyang Sun

Hui Liu

Affiliations

Soon will be listed here.

Abstract

Purpose: The purpose of this study was to investigate the remodeling of the multiple myeloma microenvironment after B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy.

Experimental Design: We performed single-cell RNA sequencing on paired bone marrow specimens (n = 14) from seven patients with multiple myeloma before (i.e., baseline, "day -4") and after (i.e., "day 28") lymphodepleted BCMA CAR-T cell therapy.

Results: Our analysis revealed heterogeneity in gene expression profiles among multiple myeloma cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells, enhanced CD8+ effector T-cell cytotoxic activity, and elevated type 1 conventional dendritic cell (DC) antigen presentation ability. DC re-clustering inferred intramedullary-originated type 3 conventional DCs with extramedullary migration. Cell-cell communication network analysis indicated that BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway-mediated immunosuppression and activates MIF pathway-mediated anti-multiple myeloma immunity.

Conclusions: Our study sheds light on multiple myeloma microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

Citing Articles

Strategies to Overcome Antigen Heterogeneity in CAR-T Cell Therapy.

Zhang B, Wu J, Jiang H, Zhou M Cells. 2025; 14(5).

PMID: 40072049 PMC: 11899321. DOI: 10.3390/cells14050320.

Unveiling the cellular landscape: insights from single-cell RNA sequencing in multiple myeloma.

Li X, Lin Z, Zhao F, Huang T, Fan W, Cen L Front Immunol. 2024; 15:1458638.

PMID: 39281682 PMC: 11392786. DOI: 10.3389/fimmu.2024.1458638.

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