Dynamics of central and peripheral immunomodulation in a murine glioma model
Open Access
- 18 February 2009
- journal article
- Published by Springer Nature in BMC Immunology
- Vol. 10 (1) , 11
- https://doi.org/10.1186/1471-2172-10-11
Abstract
Background: Immunosuppression by gliomas contributes to tumor progression and treatment resistance. It is not known when immunosuppression occurs during tumor development but it likely involves cross-talk among tumor cells, tumor-associated macrophages and microglia (TAMs), and peripheral as well as tumor-infiltrating lymphocytes (TILs). Results: We have performed a kinetic study of this immunomodulation, assessing the dynamics of immune infiltration and function, within the central nervous system (CNS) and peripherally. PDGF-driven murine glioma cells were injected into the white matter of 13 mice. Four mice were sacrificed 13 days post-injection (dpi), four mice at 26 dpi, and five mice at 40 dpi. Using multiparameter flow cytometry, splenic T cells were assessed for FoxP3 expression to identify regulatory T cells (Tregs) and production of IFN-γ and IL-10 after stimulation with PMA/ionomycin; within the CNS, CD4+ TILs were quantified, and TAMs were quantified and assessed for TNF-α and IL-10 production after stimulation with LPS. Peripheral changes associated with tumor development were noted prior to effects within the CNS. The percentage of FoxP3+ regulatory T cells (Tregs) increased by day 26, with elevated frequencies throughout the duration of the study. This early increase in Tregs was paralleled by an increase in IL-10 production from Tregs. At the final time points examined (tumor morbidity or 40 dpi), there was an increase in the frequency of TAMs with decreased capacity to secrete TNF-α. An increase in TIL frequency was also observed at these final time points. Conclusion: These data provide insight into the kinetics of the immunosuppressive state associated with tumor growth in a murine model of human gliomas. Functional impairment of TAMs occurs relatively late in the course of GBM tumor growth, potentially providing a window of opportunity for therapeutic strategies directed towards preventing their functional impairment.Keywords
This publication has 35 references indexed in Scilit:
- Incidence and Prognostic Impact of FoxP3+ Regulatory T Cells in Human GliomasClinical Cancer Research, 2008
- Immunotherapy of malignant brain tumorsImmunological Reviews, 2008
- Current Immunotherapeutic Strategies for Central Nervous System TumorsSurgical Oncology Clinics of North America, 2007
- Defective Receptor Expression and Dendritic Cell Differentiation of Monocytes in GlioblastomasNeurosurgery, 2006
- CNS immune privilege: hiding in plain sightImmunological Reviews, 2006
- Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunityImmunology, 2006
- The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1Neuro-Oncology, 2006
- An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme1Neuro-Oncology, 2006
- CD8+ T‐cell memory in tumor immunology and immunotherapyImmunological Reviews, 2006
- The trends in incidence of primary brain tumors in the population of rochester, minnesotaAnnals of Neurology, 1995