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Updated: Nov 22, 2025
Author Spotlight: Exploring Strategies for Successful Immune Response Against Tumors
Published on: August 16, 2024
Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma
Oksana Zavidij1,2,3, Nicholas J Haradhvala3,4,5, Tarek H Mouhieddine1,2,3
1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
Insights
Early immune changes in Multiple Myeloma (MM) precursor stages reveal potential biomarkers. Natural killer (NK) cells increase, while cytotoxic T-cells decline, offering new avenues for patient stratification.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Multiple Myeloma (MM) progression involves complex interactions within the tumor microenvironment.
- Early molecular characterization of precursor stages like MGUS and SMM is crucial for risk stratification and treatment.
- Understanding immune system alterations is key to developing effective immunotherapies.
Purpose of the Study:
- To comprehensively characterize the molecular and immune changes during the evolution of Multiple Myeloma (MM) from precursor stages to full-blown disease.
- To identify early immune cell alterations that can serve as biomarkers for patient stratification.
- To investigate the functional role of specific immune cells in MM immunosurveillance.
Main Methods:
- Single-cell RNA sequencing of bone marrow cells from patients at various MM stages (MGUS, SMM, MM) and healthy donors.
- Analysis of immune cell populations, including Natural Killer (NK) cells, T-cells, and monocytes.
- Functional assays, including in vitro T-cell suppression assays and in vivo mouse models of MM.
Main Results:
- Increased Natural Killer (NK) cell abundance observed in early MM precursor stages, correlated with altered chemokine receptor expression.
- Early loss of Granzyme K-positive (GrK+) memory cytotoxic T-cells identified as early as Smoldering Myeloma (SMM).
- Dysregulation of MHC class II on CD14+ monocytes leading to T-cell suppression in vitro, and a critical role of cytotoxic T-cells in MM immunosurveillance demonstrated in mouse models.
Conclusions:
- The study provides a detailed molecular map of immune system evolution during pre-malignant Multiple Myeloma (MM).
- Identified immune changes, such as NK cell abundance and cytotoxic T-cell loss, can aid in early patient stratification.
- These findings support the development of immune-based strategies for managing and treating patients at risk of MM progression.
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