The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma

Qi, Yuanlin; Zhang, Xin; Ye, Hongxing; Wang, Yin; Du, Zunguo; Yu, Yao; Mao, Ying

doi:10.1007/s11060-013-1314-0

Cited by 67 publications

(50 citation statements)

References 33 publications

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“…However, the findings of these studies were not consistent (El Andaloussi and Lesniak, 2006; Heimberger et al , 2008; Lohr et al , 2011; Kim et al , 2012; Yue et al , 2013). Because of the wide application of standard radiotherapy and/or chemotherapy for the treatment of glioma patients, the effect of immune factors on clinical outcome and the potential prognostic value of TILs are important clinical issues that need to be elucidated.…”

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confidence: 76%

Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma

et al. 2014

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Background:T lymphocyte infiltration has been detected in glioma, although its significance remains unclear. The purpose of the present study was to explore the prognostic value of CD4+ and CD8+ tumour-infiltrating lymphocytes (TILs) in glioma, and the prognostic value of infiltrating Forkhead box protein 3 (FoxP3+) regulatory T cells were also investigated.Methods:CD4+, FoxP3+ and CD8+ TILs were assessed by immunohistochemical staining of tissue microarray cores from 284 gliomas. Kaplan–Meier analysis and Cox proportional hazards models were used to examine the survival function of these TILs in 90 glioblastoma patients.Results:The number of CD8+ TILs was inversely correlated with tumour grade (P=0.025), whereas the number of CD4+ TILs was positively correlated with tumour grade (P=0.002). FoxP3+ TILs were only observed in glioblastomas, but not in low-grade astrocytomas or oligodendroglial tumours. Among patients with glioblastoma, none of CD4+ TILs, FoxP3+ TILs and CD8+ TILs alone was significantly associated with patient prognosis. However, the presence of high CD4+ and low CD8+ TIL levels was an independent predictor of poor progress-free survival (multivariate hazard ratio (HR) 1.618, 95% confidence interval (CI) 1.245–2.101, P<0.001) and poor overall survival (multivariate HR 1.508, 95% CI 1.162–1.956, P=0.002). Moreover, pseudoprogression was more often found in patients with high CD4+ TILs and high CD8+ TILs.Conclusions:The combination of CD4+ and CD8+ TILs is a predictor of clinical outcome in glioblastoma patients, and a high level of CD4+ TILs combined with low CD8+ TILs was associated with unfavourable prognosis.

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confidence: 76%

Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma

et al. 2014

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“…78 TILs have been reported to correlate with survival times in glioblastoma; however, the studies that reported this correlation were small and retrospective in nature, meaning that the finding should be validated in further investigations. 76,77 Future studies should also investigate whether density or composition of TIL infiltrates could be used as predictive biomarkers for response to immunomodulatory therapy in glioblastoma.…”

Section: The Immune System and Glioblastomamentioning

confidence: 99%

Prospects of immune checkpoint modulators in the treatment of glioblastoma

et al. 2015

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Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15–17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

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“…Similarly, the presence of tumour infiltrating lymphocytes has been described as improving prognosis, although the rate of infiltration is low [73]. In support of an important role of Tregs in glioma is an immunohistochemistry study comprising 62 patients, whose tumours were stained for FoxP3 and CD8 and found Treg accumulation at the tumour site was associated with poorer prognosis, while CD8 + tumour infiltrating lymphocytes (TILs) were not associated with increased survival [74]. Indeed, the nTreg population may predominate in glioma, with high FoxP3 expression also seen by another group in glioma samples and linked with higher grade and high levels of Helios transcription factor, another nTreg marker [75,76].…”

Section: T-cell Dysfunctionmentioning

confidence: 98%

Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma

Adhikaree

Moreno-Vicente

Kaur

et al. 2020

Cells

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Glioblastoma (GBM) is inevitably refractory to surgery and chemoradiation. The hope for immunotherapy has yet to be realised in the treatment of GBM. Immune checkpoint blockade antibodies, particularly those targeting the Programme death 1 (PD-1)/PD-1 ligand (PD-L1) pathway, have improved the prognosis in a range of cancers. However, its use in combination with chemoradiation or as monotherapy has proved unsuccessful in treating GBM. This review focuses on our current knowledge of barriers to immunotherapy success in treating GBM, such as diminished pre-existing anti-tumour immunity represented by low levels of PD-L1 expression, low tumour mutational burden and a severely exhausted T-cell tumour infiltrate. Likewise, systemic T-cell immunosuppression is seen driven by tumoural factors and corticosteroid use. Furthermore, unique anatomical differences with primary intracranial tumours such as the blood-brain barrier, the type of antigen-presenting cells and lymphatic drainage contribute to differences in treatment success compared to extracranial tumours. There are, however, shared characteristics with those known in other tumours such as the immunosuppressive tumour microenvironment. We conclude with a summary of ongoing and future immune combination strategies in GBM, which are representative of the next wave in immuno-oncology therapeutics.

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The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma

Cited by 67 publications

References 33 publications

Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma

Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma

Prospects of immune checkpoint modulators in the treatment of glioblastoma

Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma

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