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Published on: January 20, 2019
The Involvement of LAG-3positive Plasma Cells in the Development of Multiple Myeloma
Natalia Kreiniz1,2, Nasren Eiza3, Tamar Tadmor1,2
1The Division of Hematology, Bnai Zion Medical Center, Sderot Eliyahu Golomb 47, Haifa 3339419, Israel.
Abstract:
The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138+) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8+T cells were incubated with sorted LAG-3pos or LAG-3neg PCs for 24 h. The expression of granzyme (Grz) in CD8+T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8+T cells incubated with CD138+LAG-3pos PCs, compared to CD138+LAG-3neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8+T cells.
Insights
Lymphocyte-Activation Protein 3 (LAG-3) is elevated on plasma cells (PCs) in multiple myeloma (MM). Increased LAG-3 on PCs reduces CD8+ T-cell granzyme, potentially aiding MM development from premalignant conditions.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Lymphocyte-Activation Protein 3 (LAG-3) is an inhibitory receptor found on regulatory plasma cells (PCs).
- Increased expression of LAG-3 on micro-environmental cells correlates with the progression of smoldering multiple myeloma (SMM).
Purpose of the Study:
- To investigate the role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia.
- To determine if LAG-3 on PCs influences T-cell activity in multiple myeloma (MM).
Main Methods:
- Flow cytometry was used to analyze LAG-3 expression on purified Cluster of Differentiation 138 (CD138+) PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), SMM, active MM, and healthy controls.
- Autologous CD8+ T-cells were co-cultured with sorted LAG-3 positive (LAG-3pos) or LAG-3 negative (LAG-3neg) PCs.
- Granzyme (Grz) expression in CD8+ T-cells was quantified via flow cytometry.
Main Results:
- LAG-3 expression on PCs was significantly higher in active MM patients (newly diagnosed and relapsed/refractory) compared to those with MGUS/SMM.
- CD8+ T-cells incubated with LAG-3pos PCs showed significantly decreased Grz expression compared to those incubated with LAG-3neg PCs (p = 0.0041).
Conclusions:
- LAG-3 expression on malignant PCs is elevated in active multiple myeloma.
- LAG-3 on malignant PCs may contribute to the pathogenesis of MM from MGUS by suppressing CD8+ T-cell cytotoxic function through reduced granzyme expression.
