Abstract
Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies.
Highlights
Interactions between cancer and the immune system have been proposed to rely on three processes: elimination, equilibrium, and escape, leading to immunologic sculpting of the tumor
CD45 expression was lower in resident resting microglia than in other brain-infiltrating leukocytes (BIL) and was not detected by immunohistochemistry
Analyses of human malignant astrocytoma and intracranially implanted mouse models highlight the complexity of interactions between the immune system and gliomas
Summary
Interactions between cancer and the immune system have been proposed to rely on three processes: elimination (immunosurveillance), equilibrium, and escape, leading to immunologic sculpting of the tumor (immunoediting). Evidence for these mechanisms comes from mouse models, observation of large cohorts of immunosuppressed patients showing increased cancer incidence, and in certain tumors, correlation between immune infiltration and clinical outcome [1,2,3]. An antiglioma immune infiltrate appearing earlier might shape the tumor to develop less immunogenic variants or immune escape mechanisms These issues must be studied in the context of the brain, as this site www.aacrjournals.org imposes such a specialized interface between cancer and the immune system
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