Dynamics of central and peripheral immunomodulation in a murine glioma model.
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-gamma and IL-10 after stimulation with PMA/ionomycin; within the CNS, CD4+ TILs were quantified, and TAMs were quantified and assessed for TNF-alpha 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-alpha. An increase in TIL frequency was also observed at these final time points.


CONCLUSIONS
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.
Kennedy
Benjamin C
BC
Department of Neurosurgery, Gabriele Bartoli Brain Tumor Research Laboratory Columbia University, New York, NY, USA. bck2104@columbia.edu
Maier
Lisa M
LM
D'Amico
Randy
R
Mandigo
Christopher E
CE
Fontana
Elizabeth J
EJ
Waziri
Allen
A
Assanah
Marcela C
MC
Canoll
Peter
P
Anderson
Richard C E
RC
Anderson
David E
DE
Bruce
Jeffrey N
JN
D000818:Animals; D001932:Brain Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens; D002465:Cell Movement / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma