Related Experiment Video
Updated: Mar 18, 2026
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic
Tithi Ghosh1, Subhasis Barik1, Avishek Bhuniya1
1Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, West Bengal, 700026, India.
Abstract:
Mesenchymal stem cells (MSCs) represent an important cellular constituent of the tumor microenvironment, which along with tumor cells themselves, serve to regulate protective immune responses in support of progressive disease. We report that tumor MSCs prevent the ability of dendritic cells (DC) to promote naïve CD4(+) and CD8(+) T cell expansion, interferon gamma secretion and cytotoxicity against tumor cells, which are critical to immune-mediated tumor eradication. Notably, tumor MSCs fail to prevent DC-mediated early T cell activation events or the ability of responder T cells to produce IL-2. The immunoregulatory activity of tumor MSCs is IL-10- and STAT3-dependent, with STAT3 repressing DC expression of cystathionase, a critical enzyme that converts methionine-to-cysteine. Under cysteine-deficient priming conditions, naïve T cells exhibit defective cellular metabolism and proliferation. Bioinformatics analyses as well as in vitro observations suggest that STAT3 may directly bind to a GAS-like motif within the cystathionase promoter (-269 to -261) leading to IL-10-STAT3 mediated repression of cystathionase gene transcription. Our collective results provide evidence for a novel mechanism of tumor MSC-mediated T cell inhibition within tumor microenvironment.
Insights
Tumor mesenchymal stem cells (MSCs) inhibit T cell responses critical for tumor eradication by reducing cysteine availability. This novel mechanism involves IL-10 and STAT3 signaling, impacting T cell metabolism and proliferation.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Mesenchymal stem cells (MSCs) are key components of the tumor microenvironment.
- MSCs influence immune responses, often supporting tumor progression.
Purpose of the Study:
- To investigate the mechanism by which tumor-associated MSCs suppress anti-tumor T cell immunity.
- To identify key molecular players in MSC-mediated immune evasion.
Main Methods:
- Co-culture of MSCs with dendritic cells (DCs) and T cells.
- Analysis of T cell expansion, cytokine secretion (IFN-γ, IL-2), and cytotoxicity.
- Assessment of STAT3 and IL-10 signaling pathways.
- Investigation of cystathionase expression and activity in DCs.
- Bioinformatics analysis of STAT3 binding to the cystathionase promoter.
Main Results:
- Tumor MSCs inhibit naive CD4(+) and CD8(+) T cell expansion, IFN-γ secretion, and cytotoxicity.
- MSCs do not inhibit early T cell activation or IL-2 production.
- MSC-mediated inhibition is dependent on IL-10 and STAT3.
- STAT3 represses DC cystathionase expression, leading to cysteine deficiency.
- Cysteine-deficient T cells show impaired metabolism and proliferation.
Conclusions:
- Tumor MSCs employ a novel mechanism to inhibit anti-tumor T cell immunity by disrupting cysteine metabolism.
- The IL-10-STAT3-cystathionase axis is crucial for MSC-mediated immune suppression.
- Targeting this pathway could restore anti-tumor T cell function.
Related Concept Videos
01:19Mesenchymal Stem Cells
02:40Cancer Stem Cells and Tumor Maintenance
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
02:17The Tumor Microenvironment
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...