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Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation
Farah Ahmady1,2, Peter Curpen3, Louis Perriman1,2,4
1Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia.
Abstract:
Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4+ and CD8+ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4+ and CD8+ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.
Insights
Glioblastoma elevates TIM-3 expression on immune cells, reducing anti-tumor activity. BAT3 levels decrease, correlating with suppressed T and NK cell function, highlighting immune evasion mechanisms.
Area of Science:
- Immunology
- Oncology
- Neuro-oncology
Background:
- Immune checkpoint and inhibitory receptors regulate immune cell function.
- Over-expression of these receptors on T and NK cells impairs anti-tumor activity in cancer.
- Glioblastoma (GBM) is an aggressive brain tumor with a poorly understood immune microenvironment.
Purpose of the Study:
- To investigate the expression and role of inhibitory receptors in glioblastoma.
- To identify specific inhibitory receptors and associated molecules contributing to immune suppression in GBM.
- To elucidate the mechanisms of T cell and NK cell dysfunction in the GBM tumor microenvironment.
Main Methods:
- Analysis of gene expression for 11 checkpoint and inhibitory receptors in GBM.
- Flow cytometry to assess cell surface protein expression on T cells (CD4+, CD8+) and NK cells from GBM patients and healthy donors.
- Evaluation of co-stimulatory/co-inhibitory molecules, activation markers (CD69), and cytokines (IFNγ).
Main Results:
- HAVCR2 (TIM-3) and ENTPD1 (CD39) showed significantly higher gene expression in GBM.
- Cell surface TIM-3 was elevated on T cells and NK cells in GBM patients.
- Reduced BAT3 expression and lower CD69 and IFNγ levels were observed in GBM patient immune cells, correlating with TIM-3 dysregulation.
Conclusions:
- Glioblastoma exhibits dysregulated expression of TIM-3 and BAT3 on immune cells.
- These changes contribute to the suppression of CD4+, CD8+ T cells, and NK cells in GBM.
- Targeting TIM-3 and BAT3 pathways may restore anti-tumor immunity in glioblastoma.
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