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Updated: Sep 13, 2025
Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies
Published on: November 10, 2023
The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma
Yun Wang1, Shuzhao Chen2, Zhijian Liang3
1Department of Hematological Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Centre for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China. wangyun@sysucc.org.cn.
Abstract:
Daratumumab, an anti-CD38 monoclonal antibody, is an effective therapy for plasma cell myeloma (PCM). However, many initial responders relapse. We compared paired samples from subjects pre-therapy and then acquired resistance to daratumumab. We first used single-cell RNA sequencing and digital spatial profiler (DSP). The proportion of cytotoxic CD8-positive T-cells with an exhaustion phenotype and an IFN-γ signature increased in resistance compared with pre-therapy samples, whilst the proportion of NK-cells decreased and had an increased inhibitory phenotype. Transcription of CD38 in neoplastic plasma cells decreased. Numbers of immune cells in cancer centre defined by DSP were significantly decreased in parallel with an increased exhaustion signature. The acquired resistance signature and elevated PCM subset phenotype were associated with worse prognosis in 4 external cohorts (GSE24080, GSE136337, GSE57317, and coMMpass). Using single-cell regulatory network inference, we identified MYC regulation as a key activated factor for acquired resistance in neoplastic plasma cells by intersecting the top 20 upregulated regulons and upregulated genes in acquired resistance. Furthermore, data from in vitro and in vivo experiments indicate that IFN-γ secreted by cells of bone marrow immune ecosystem activates MYC, which correlates with acquired daratumumab resistance. Our data provide insights into acquired daratumumab resistance and suggest potential therapeutic strategies.
Insights
Daratumumab resistance in plasma cell myeloma involves increased T-cell exhaustion and decreased NK-cells. MYC activation, driven by IFN-γ, is a key factor in acquired resistance to this anti-CD38 therapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Daratumumab, an anti-CD38 antibody, is effective against plasma cell myeloma (PCM).
- Acquired resistance limits long-term efficacy, necessitating understanding of resistance mechanisms.
Purpose of the Study:
- To investigate the immune microenvironment and molecular changes associated with acquired daratumumab resistance in PCM.
- To identify key regulatory pathways driving resistance for potential therapeutic targeting.
Main Methods:
- Comparative analysis of paired pre-therapy and resistant samples using single-cell RNA sequencing and digital spatial profiling (DSP).
- In vitro and in vivo experiments to validate identified resistance mechanisms.
- Bioinformatic analysis including single-cell regulatory network inference.
Main Results:
- Acquired resistance showed increased cytotoxic CD8-positive T-cells with exhaustion phenotypes and decreased NK-cells with inhibitory phenotypes.
- Decreased CD38 transcription in neoplastic plasma cells and reduced immune cell infiltration were observed.
- MYC regulation was identified as a key activated factor in neoplastic plasma cells, linked to IFN-γ secretion and daratumumab resistance.
- Resistance signature correlated with worse prognosis in external patient cohorts.
Conclusions:
- Acquired daratumumab resistance in PCM is characterized by specific immune cell alterations and MYC pathway activation.
- IFN-γ signaling in the bone marrow immune ecosystem plays a crucial role in promoting MYC-driven resistance.
- These findings offer insights into resistance mechanisms and suggest potential therapeutic strategies targeting MYC or immune modulation.
