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Published on: January 6, 2014
Induction of Immunogenic Cell Death in Lymphoma Cells by Wharton's Jelly Mesenchymal Stem Cell Conditioned Medium
Daniel Hao Lin1, Arijit Biswas1, Mahesh Choolani1
1Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Kent Ridge, Singapore, 119228, Singapore.
Abstract:
Strategies that induce immunogenic cell death (ICD) or downregulate CD47 or PD-L1 expression have resulted in successful therapeutic options for tumor eradication. Several groups have reported the tumoricidal effects of human umbilical cord Wharton's jelly stem cells (hWJSCs) or its conditioned medium (hWJSC-CM) on certain cancers but the mechanisms have not been elucidated. Since hWJSCs possess immunomodulatory properties, we investigated whether one of the tumoricidal mechanisms was via ICD. We first concentrated hWJSC-CM into a 3 kDa concentrate and then exposed various concentrations of this concentrate to human lymphoma cells to find out which concentration had the greatest tumoricidal effect. We observed that a 500 µg/ml concentration of the concentrate had the greatest inhibitory effect. Thereafter, lymphoma cells were exposed to 500 µg/ml of the hWJSC-CM-3 kDa concentrate and then subjected to analysis for morphology, viability, apoptosis, mitochondrial and endoplasmic reticulum stress, danger associated molecular patterns (DAMP), extracellular HMGB1, CD47 and PD-L1 markers and dendritic cell phenotype. Extensive nuclear chromatin and mitochondrial changes with significantly decreased cell viability and increased apoptosis were observed in the treated lymphoma cells compared to controls. There were also significant increases in the release of DAMPs, extracellular HMGB1 and dendritic cell activation and maturation, with concomitant decreases in CD47 and PD-L1 expression in the treated cells compared to controls. In other ongoing studies we observed increased expression of specific tumor-suppressor molecules (miRNA-146a and miRNA-126, MCP-1, IL-6, IL-8 and IL-12) in hWJSC-CM suggesting that one or more of these molecules may be the modulators of the ICD.
Insights
Human umbilical cord stem cells induce immunogenic cell death (ICD) in lymphoma cells, decreasing CD47 and PD-L1 expression. This suggests a novel therapeutic mechanism for tumor eradication via stem cell therapy.
Area of Science:
- Immunology
- Stem Cell Biology
- Oncology
Background:
- Therapeutic strategies targeting tumor eradication include inducing immunogenic cell death (ICD) or downregulating CD47 and PD-L1 expression.
- Human umbilical cord Wharton's jelly stem cells (hWJSCs) and their conditioned medium (hWJSC-CM) have demonstrated tumoricidal effects, but the underlying mechanisms remain unclear.
- Given the known immunomodulatory properties of hWJSCs, this study investigated their potential to induce ICD in cancer cells.
Purpose of the Study:
- To elucidate the mechanisms behind the tumoricidal effects of hWJSC-CM.
- To determine if hWJSC-CM induces immunogenic cell death (ICD) in human lymphoma cells.
- To analyze the impact of hWJSC-CM on cancer cell viability, apoptosis, stress markers, and immune checkpoint proteins (CD47, PD-L1).
Main Methods:
- Concentrated hWJSC-CM (3 kDa) was applied to human lymphoma cells at various concentrations to identify the optimal tumoricidal dose.
- Lymphoma cells treated with the optimal hWJSC-CM concentration were analyzed for morphological and viability changes, apoptosis, mitochondrial and endoplasmic reticulum stress.
- Analysis included the assessment of danger-associated molecular patterns (DAMPs), extracellular HMGB1, CD47 and PD-L1 expression, and dendritic cell activation.
Main Results:
- A concentration of 500 µg/ml of the hWJSC-CM concentrate exhibited the most significant inhibitory effect on lymphoma cells.
- Treatment led to substantial nuclear chromatin and mitochondrial alterations, decreased cell viability, and increased apoptosis.
- Significant increases in DAMPs and extracellular HMGB1 were observed, alongside enhanced dendritic cell activation and maturation. Concurrently, CD47 and PD-L1 expression decreased.
Conclusions:
- hWJSC-CM effectively induces immunogenic cell death (ICD) in human lymphoma cells.
- The observed decrease in CD47 and PD-L1 expression suggests a potential role for hWJSC-CM in overcoming immune evasion mechanisms in cancer.
- Ongoing studies indicate that tumor-suppressor molecules within hWJSC-CM may mediate these ICD effects, highlighting a promising avenue for cancer immunotherapy.
