Interferon-α/β enhances temozolomide activity against MGMT-positive glioma stem-like cells

Shen, Dong; Guo, Cheng; Wang, Jing; Qiu, Zhi Kun; Sai, Ke; Yang, Qun; Chen, Yin Sheng; Chen, Fu‐Rong; Wang, Jie; Panasci, Lawrence C.; Chen, Zhong Ping

doi:10.3892/or.2015.4232

Cited by 35 publications

(23 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, a clinical trial demonstrated that combination treatment involving TMZ and the cytokines IFN-α/β did not significantly improve the overall prognosis of glioma patients. 37 In the present study, after poly(I:C) was delivered to the brain by the IN route, IFN-I production peaked on day 13 and remained at a high level until day 21 ( Figure 4B-D), and anti-tumor immunity was ultimately activated. This finding implies that continuous cancer cell-autonomous IFN-I signaling is required for ICD.…”

supporting

confidence: 49%

<p>Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response</p>

Yin¹,

Li²,

Ke³

et al. 2020

IJN

View full text Add to dashboard Cite

Purpose: Some chemotherapeutics have been shown to induce both the release of damageassociated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain. Methods: A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumorbearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses. Results: Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group. Conclusion: This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.

show abstract

supporting

confidence: 49%

<p>Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response</p>

Yin¹,

Li²,

Ke³

et al. 2020

IJN

View full text Add to dashboard Cite

show abstract

“…IHC staining was performed as reported previously 35 . The expression level of TNC in glioma tissues was scored as the proportion of the area with positive staining (0-100%) multiplied by the staining intensity (0, negative; 1, weak; 2, moderate; 3, intense).…”

Section: Immunohistochemical (Ihc) Stainingmentioning

confidence: 99%

“…The role of TNC in glioma cell proliferation was evaluated via cell growth assays, as reported previously 35 . Briefly, 5000 cells were seeded in each well in 6-well plates.…”

Section: Proliferation Assaymentioning

confidence: 99%

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Cai

Wang

et al. 2019

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser 473 and Thr 308 and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.

show abstract

“…Multiple studies, including our own, have evaluated the combination of IFN-β with Temozolomide (TMZ), the standard-of-care chemotherapeutic for GBM patients 42 (on mature GBM cells and Glioma stem cells both in culture and in vivo 41,43–47 ). Such combination therapy was also evaluated on GBM patients 48, 49 .…”

Section: Discussionmentioning

confidence: 99%

Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery

et al. 2018

View full text Add to dashboard Cite

The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.

show abstract

Interferon-α/β enhances temozolomide activity against MGMT-positive glioma stem-like cells

Cited by 35 publications

References 29 publications

<p>Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response</p>

<p>Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response</p>

Tenascin-c mediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma

Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery

Contact Info

Product

Resources

About