Incidence and Prognostic Impact of FoxP3+ Regulatory T Cells in Human Gliomas

Abstract

Purpose: The incidence of regulatory T cells (Treg) in intrinsic central nervous system malignancies is unknown. Immunotherapeutic approaches that inhibit the Treg population may be limited to a subset of patients with gliomas. Our hypothesis is that only the most malignant gliomas have a prominent glioma-infiltrating Treg population that contributes to the immunosuppressive biology and that the presence of Tregs is a negative prognostic variable. Experimental Design: We measured the incidence of Tregs in 135 glial tumors (including all pathologic types) in a glioma microarray using immunohistochemical analysis. Results were categorized according to the total number of Tregs within the tumors. Correlation of the presence of Tregs with prognosis was evaluated using univariate and multivariate analyses. Results: Tregs were not present in normal brain tissue and were very rarely found in low-grade gliomas and oligodendrogliomas. We observed significant differences in the prevalence of Tregs between astrocytic and oligodendroglial tumors, between tumors of different grades, and between different pathologic types of tumors. We identified Tregs most frequently in glioblastoma multiforme (GBM) but very rarely in low-grade astrocytomas. The presence of Tregs within GBMs did not alter the median survival in patients from whom the tumors were obtained. Conclusions: Treg infiltration differed significantly in the tumors according to lineage, pathology, and grade. Tregs seemed to have the highest predilection for tumors of the astrocytic lineage and specifically in the high-grade gliomas, such as GBM. In both univariate and multivariate analysis, the presence of Tregs in GBMs seemed to be prognostically neutral.

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

“…Heimberger et al (22) and Grabenbauer et al (23) investigated local tumor-infiltrating lymphocytes using tissue microarrays. Their conclusions, however, were conflicting, despite their studies being performed under almost identical conditions and using identical protocols.…”

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

“…Interestingly, previous studies have shown greater immunosuppressive activity of T regs associated with CNS tumors (31)(32)(33). The transcription factor Foxp3 plays a crucial role in immune homeostasis and T reg development (34)(35)(36), as demonstrated by the dramatic autoimmune phenotype of the Foxp3 forkhead domain-deficient Scurfy mouse (37), and autoimmune disease in humans bearing Foxp3 mutations known as immunodysregulation polyendocrinopathy enteropathy X-linked syndrome.…”

Characterization of Immune Cell Infiltration Into Canine Intracranial Meningiomas

“…7 Regulatory T cells have recently been shown to play an important role in the progression of a variety of different neoplasms, 74 including gliomas. 30,33 Small numbers of FoxP3 þ cells were documented in a subset of the canine meningiomas in this study, suggesting that Tregs may be playing a role in tumor escape from the immune system in these patients.…”

“…32 Populations of Tregs have been shown to contribute to immune escape in a variety of cancers, 74 and recent studies have also shown these cells in human brain tumors. 30,33 Toll-like receptors (TLRs) on the surface of immune cells recognize a variety of microbial molecular patterns, and they initiate immune and inflammatory responses through several signal transduction pathways. For example, TLR4 recognizes lipopolysaccharide (LPS), and TLR9 recognizes unmethylated cytosine-guanine dinucleotide (CpG) motifs characteristic of bacteria.…”