HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment

Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang‐Fan; Mizraji, Gabriel; Levin, Anat Globerson; Sliwkowski, Mark X.; Levitzki, Alexander

doi:10.1158/2326-6066.cir-15-0203

Cited by 9 publications

(15 citation statements)

References 46 publications

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“…In our previous studies we employed chemical vectors that bind PolyIC electrostatically, and utilize EGF or anti-HER2 affibody as homing entities towards EGFR or HER2 [15–18]. …”

Section: Introductionmentioning

confidence: 99%

Targeting polyIC to EGFR over-expressing cells using a dsRNA binding protein domain tethered to EGF

et al. 2016

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Selective delivery of drugs to tumor cells can increase potency and reduce toxicity. In this study, we describe a novel recombinant chimeric protein, dsRBEC, which can bind polyIC and deliver it selectively into EGFR over-expressing tumor cells. dsRBEC, comprises the dsRNA binding domain (dsRBD) of human PKR (hPKR), which serves as the polyIC binding moiety, fused to human EGF (hEGF), the targeting moiety. dsRBEC shows high affinity towards EGFR and triggers ligand-induced endocytosis of the receptor, thus leading to the selective internalization of polyIC into EGFR over-expressing tumor cells. The targeted delivery of polyIC by dsRBEC induced cellular apoptosis and the secretion of IFN-β and other pro-inflammatory cytokines. dsRBEC-delivered polyIC is much more potent than naked polyIC and is expected to reduce the toxicity caused by systemic delivery of polyIC.

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“…In our previous studies we employed chemical vectors that bind PolyIC electrostatically, and utilize EGF or anti-HER2 affibody as homing entities towards EGFR or HER2 [15–18]. …”

Section: Introductionmentioning

confidence: 99%

Targeting polyIC to EGFR over-expressing cells using a dsRNA binding protein domain tethered to EGF

et al. 2016

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“…Our previous studies focused on the use of chemical vectors to target polyIC to EGFR-and HER2-overexpressing cancer cells [14,33]. Proteins have several potential advantages as therapeutics over chemical compounds, as proteins function in a highly specific manner and feature consistent structures and low immunogenicity [34,46].…”

Section: Discussionmentioning

confidence: 99%

“…In our laboratory we have developed chemical vectors to deliver polyIC to EGFR-overexpressing glioblastoma [32], breast cancer and vulval carcinoma [14], as well as HER-2-overexpressing breast cancer [33]. The targeted polyIC proved to be extremely efficient at killing tumors in vitro and in vivo, leading in some cases to complete tumor eradication [14,32].…”

Section: Priority Research Papermentioning

confidence: 99%

“…All cell lines were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA), tested and shown to be mycoplasma-free. LNCaP-Luc/GFP and PC3-Luc/GFP were generated using lentiviral vectors encoding the fusion gene luciferase-GFP (Luc/GFP) as previously described [33]. PBMCs were isolated from fresh human peripheral blood by standard Ficoll densitygradient centrifugation [14].…”

Section: Dsrb-scpmentioning

confidence: 99%

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2017

Oncotarget

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“…9 In normal keratinocytes, which are host cells of HPV, extracellular poly(I:C) stimulation greatly induced inflammatory mediator expression, including tumour necrosis factor α and type I IFNs, therefore promoting the activation of dendritic cells. In cancer vaccination, tumour-derived nucleic acids, such as poly(I:C), act on both tumour cells and non-malignant components, resulting in a complex interaction network.…”

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confidence: 99%

IL‐6 expression promoted by Poly(I:C) in cervical cancer cells regulates cytokine expression and recruitment of macrophages

Liu

Chen

et al. 2020

J Cellular Molecular Medi

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| INTRODUC TI ONCervical cancer is the most common gynaecological malignancy, ranking fourth in both incidence and cancer-related deaths among women worldwide. 1 Despite the advancements in prophylactic vaccines and screening programs, which have greatly decreased the incidence rate, effective therapies continue to fall short. A therapeutic vaccine, however, would likely be a promising approach in the treatment of cervical cancer by modulating the host immune system in vivo and thus provoking an anti-tumour response. Adjuvants are mandatory in cancer vaccines for their capacity to elicit a strong and persistent immune response towards tumour-associated antigens, as the immunogenicity of recombinant antigen proteins or peptides alone is usually not sufficient. Polyriboinosinic-polyribocytidylic Abstract Poly(I:C) is a promising adjuvant for cancer treatment vaccines to enhance the host anti-tumour immune response. However, the roles of poly(I:C) in the cervical cancer microenvironment and local immune reactions are not well understood. In this study, we investigated the roles of poly(I:C) in the cervical cancer. We analysed the cytokine transcription and secretion of cervical cancer cell lines and THP-1-derived macrophages after poly(I:C) treatment, respectively. These results revealed that IL-6 was significantly up-regulated, and this up-regulation was partly dose dependent. poly(I:C)stimulated supernatant of cervical cancer cells promoted M1-type cytokine IL-1β and IL-6 expression of THP-1-derived macrophages, but inhibited the expression of M2type cytokine, IL-10 and CCL22. The recruitment of THP-1-derived macrophages by poly(I:C)-stimulated cervical cancer cell supernatant was also enhanced. Inhibition of IL-6 expression in cervical cancer cells by siRNA transfection almost completely reversed the effects of poly(I:C) treatment. Finally, we found that phosphorylation of the NF-κB signalling pathway in cervical cancer cells occurred quickly after poly(I:C) treatment. Moreover, the NF-κB signalling pathway inhibitor PDTC significantly inhibited poly(I:C)-induced IL-6 expression. Taken together, these results suggest that poly(I:C) might regulate the effects of cervical cancer cells on tumour-infiltrated macrophages, and subsequently promote a pro-inflammatory tumour microenvironment. K E Y W O R D S cervical cancer cell, IL-6, macrophages, poly(I:C), recruitment S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Liu X, Meng L, Chen L, et al. IL-6 expression promoted by Poly(I:C) in cervical cancer cells regulates cytokine expression and recruitment of macrophages.

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HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment

Cited by 9 publications

References 46 publications

Targeting polyIC to EGFR over-expressing cells using a dsRNA binding protein domain tethered to EGF

Targeting polyIC to EGFR over-expressing cells using a dsRNA binding protein domain tethered to EGF

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IL‐6 expression promoted by Poly(I:C) in cervical cancer cells regulates cytokine expression and recruitment of macrophages

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