Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma

Abstract

Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Targeting Neoantigens in Glioblastoma

“…[26][27][28][29][30] Together, these data support the notion that both the humoral and cellular arms of the immune system are able to be primed against GBM antigens. However, it remains unclear by which mechanism these adaptive immune responses are generated; which antigens they recognize; the functional capacity of such naturally occurring responses; and the role these spontaneous immune responses play in driving immune escape.…”

T‐Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins

“…Regulatory T cells (T Reg ) function as critical inhibitory immunoregulatory cells [2–4] and have been reported to be increased in tumor-bearing individuals, restraining immune-mediated anti-tumor cytotoxicity [5]. Increased T Reg in solid tumors, including ovarian carcinoma [6,7], pancreatic cancer [8,9], lung cancer [10] and glioblastoma [11] have been associated with poor response to standard chemotherapy and diminished survival outcomes [5,12,13]. Increased T Reg numbers have also correlated with negative outcomes following immunotherapy treatment of malignant melanoma [14].…”

Methotrexate up-regulates ecto-5′-nucleotidase/CD73 and reduces the frequency of T lymphocytes in the glioblastoma microenvironment

“…The average survival of a patient with GBM who is undergoing the current standard chemotherapy is only 14 months [1,2]. Some reasons for treatment failure and GBM recurrence are multidrug resistance, intrinsic limitations due to the blood brain barrier (BBB), the inherent resistance of glioblastoma cancer stem cells (GSCs) to chemotherapy, and the ability of the cancer cells to escape from a compromised immune system [3,4]. In fact, although GBM has an extensive inflammatory infiltrate, the immune cells are functionally impaired, resulting in a pro-tumoral immune response [1].…”

“…The escape from the immunosurveillance is partially mediated by T-regulatory (Treg) lymphocytes that are present at high levels in the GBM microenvironment (GME). The quantity of Treg cells is associated with reduced survival and increased recurrence in GBM patients [4].…”