Immune Infiltration of Spontaneous Mouse Astrocytomas Is Dominated by Immunosuppressive Cells from Early Stages of Tumor Development

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-γ, 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-γ) 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. Cancer Res; 70(12); 4829-39. ©2010 AACR.

Intratumoral Mediated Immunosuppression is Prognostic in Genetically Engineered Murine Models of Glioma and Correlates to Immunotherapeutic Responses

“…It is possible that the FoxP3 expression was occurring within the cancer cells (59); however we confined our counts to those cells that had a lymphocyte morphology. These data, in conjunction with another study showing that the immune infiltration in spontaneous mouse astrocytomas evolved along with the stages of tumor development (60) indicate that these murine model systems may be suitable for the study of immunotherapeutic approaches because many features of tumor-mediated immunosuppression observed in these systems appear similar to those seen in human glioma patients.…”

miR-21 in the Extracellular Vesicles (EVs) of Cerebrospinal Fluid (CSF): A Platform for Glioblastoma Biomarker Development

“…Although EVs in CSF appear to be enriched for miR-21, we have little data on the sub-speciation of these EVs in terms of size, zeta potential, shape, or type [67]. Equally uncertain is the origin of CSF EV miR-21, which may be from glioblastoma or associated endothelial, ependymal or inflammatory cells [77,78]. To the extent that we consistently observed the secretion of miR-21 containing EVs from all glioblastoma cells examined, we propose that these vesicles contribute to the presence of hsa-miR-21 in the CSF.…”

Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response

“…T cells may be driven to exhaustion or anergy in response to tumors due to chronic antigen presentation at tumor sites [19,47,48]. Vaccination regimens often improve the function of T cells, indicating that natural priming against tumor antigens may be insufficient in many contexts [8,49]. Alternatively, models of pancreatic and breast cancer have shown that tumors actively recruit myeloid-derived suppressor cells (or T regulatory cells) that suppress adaptive immune responses at tumor sites [38,39,42].…”