The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression

See, Alfred P.; Parker, Jonathon J.; Waziri, Allen

doi:10.1007/s11060-015-1849-3

Cited by 54 publications

(42 citation statements)

References 73 publications

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“…As tumor‐associated microglia/macrophages (TAMs) and T cells are important components of the immune system shown to influence brain tumor growth (Kmiecik et al ., ; Li and Graeber, ; See et al ., ), we analyzed the presence of these cells in tumor‐bearing brains after treatment with AAV9/P2‐Int‐mIFN‐β vector, as the corresponding treatment cohort had the longest median survival (Fig. B).…”

Section: Resultsmentioning

confidence: 99%

Intracranial AAV‐IFN‐β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model

GuhaSarkar

Neiswender

et al. 2017

Molecular Oncology

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The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard‐of‐care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon‐beta (IFN‐β) gene therapy by locally administered adeno‐associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN‐β eliminates invasive human GBM8 tumors and promotes long‐term survival. Next, we screened five AAV‐IFN‐β vectors with different promoters to drive safe expression of mouse IFN‐β in the brain in the context of syngeneic GL261 tumors. Two AAV‐IFN‐β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2‐Int‐mIFN‐β vector. We also assessed the therapeutic effect of combining AAV‐IFN‐β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second‐strand DNA synthesis of single‐stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV‐IFN‐β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV‐IFN‐β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency.

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Section: Resultsmentioning

confidence: 99%

Intracranial AAV‐IFN‐β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model

GuhaSarkar

Neiswender

et al. 2017

Molecular Oncology

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“…The potential mechanisms of action of sTNF-R1 and sTNF-R2 have not been fully elucidated and the significantly lower mean levels of sTNF-R1 in both the newly-diagnosed and recurrent GBM patients is consistent with the profound systemic immunosuppression, involving multiple different cellular and cytokine compartments including high levels of IL-10, which is a hallmark of GBM [37–40]. The sTNF-Rs may reduce the levels of TNFα in the circulation or block its activity [1, 5, 6, 18].…”

Section: Discussionmentioning

confidence: 99%

Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

et al. 2016

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The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (p=0.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients.

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“…A variety of mechanisms to escape a tumor-specific T-cellmediated immune response have been identified in glioma and other cancer entities: (i) expression of immune checkpoint molecules inducing T-cell exhaustion, for example, through programmed death-1 (PD-1) receptor or CTLA-4 signaling (5, 6); (ii) modulation of the local tumor microenvironment by attracting regulatory T cells (Tregs) secreting immunosuppressive cytokines (7); (iii) escape from T-cell recognition caused by mutation or downregulation of HLA molecules (8); and (iv) a high degree of heterogeneity, denying a common target for the immune system (9). A major goal of current immunotherapeutic strategies is to overcome these mechanisms of T-cell suppression.…”

Section: Introductionmentioning

confidence: 99%

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Mohme

Schliffke

Maire

et al. 2018

Clinical Cancer Research

112

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Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion. We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM. We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8 TILs was defined by an increased prevalence of PD-1, CD39, Tim-3, CD45RO, HLA-DR marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8 T cells. TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. .

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The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression

Cited by 54 publications

References 73 publications

Intracranial AAV‐IFN‐β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model

Intracranial AAV‐IFN‐β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model

Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

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