DNA vaccine encoding HPV-16 E7 with mutation in L-Y-C-Y-E pRb-binding motif induces potent anti-tumor responses in mice

Bahrami, Armina Alagheband; Ghaemi, Amir; Tabarraei, Alijan; Sajadian, Azadeh; Gorji, Ali; Soleimanjahi, Hoorieh

doi:10.1016/j.jviromet.2014.05.013

Cited by 22 publications

(14 citation statements)

References 34 publications

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“…HPVs perturb cell growth, apoptosis and differentiation, however, they are additionally involved in affecting host anti-virus/tumor immune responses (17). Previous studies have reported that HPVE7 affects the innate immune response by downregulating the expression of interferon-responsive genes, which affects activation of the subsequent adaptive immune response (18,19).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

Liu

Lü

Tian

et al. 2017

Molecular Medicine Reports

105

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Cytotoxic T lymphocyte dysfunction is frequently associated with PD-L1/PD-1 pathway activation, and is a principal obstacle in cancer therapy. In the present study, the mechanisms underlying the human papillomavirus (HPV)-induced evasion of cervical cancer cells to the host immune system via the programmed death ligand 1/programmed death 1 (PD-L1/PD-1) signaling pathway was investigated. A significant increase in the expression of the HPV16E7 viral protein and PD-L1 in cervical tissues was observed when compared with normal cervical tissues. In addition, a positive correlation between HPV16E7 and PD-L1 expression was observed by immunohistochemical staining and reverse transcription-polymerase chain reaction. Overexpressing HPV16E7 oncoprotein in the epithelial carcinoma of PC3 cells increased the expression level of the PD-L1 protein and inhibited peripheral blood mononuclear cell (PBMC) proliferation and cytotoxic T lymphocyte (CTL) activity. Upon knockdown of HPV16E7 in HPV16-associated CaSki cervical cancer cells with a relevant siRNA, a reduction in PD-L1 protein expression was observed, as well as a significant increase in PBMC proliferation and CTL activity. A recombinant plasmid, MSCVPIG-soluble PD-1, was constructed and transfected into the CaSki cell line, and was co-cultured with PBMCs. PBMC proliferation and CTL activity were observed to increase significantly. In conclusion, the results presented in the current study suggest that overexpression of PD-L1, induced by HPV16E7, may be responsible for lymphocyte dysfunction. In addition, soluble PD-1 may restore the function of tumor-infiltrating lymphocytes by inhibiting the PD-L1/PD-1 signaling pathway. These results may provide a novel insight for immunotherapeutic approaches in the treatment of cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

Liu

Lü

Tian

et al. 2017

Molecular Medicine Reports

105

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“…In the present study, an improved vaccine was constructed that includes the E6 and E7 antigens, which provides a better antitumor effect according to the literature (15–17). In addition, the two antigens were mutant versions to eliminate the risk of cellular transformation (18,19) and were codon-optimized for efficient expression in mammalian cells (20). These antigens were fused to the human CRT signal peptide and the KDEL signal (SP-E6E7m-KDEL).…”

Section: Introductionmentioning

confidence: 99%

DNA vaccine encoding human papillomavirus antigens flanked by a signal peptide and a KDEL sequence induces a potent therapeutic antitumor effect

et al. 2017

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Cellular immune responses play a critical role in the eradication of intracellular infections and malignant cells through the recognition and subsequent removal of the infection or malignant cells. Effective antigen presentation is crucial for stimulating the immune system against malignant cells. Calreticulin (CRT) has been used to improve antigen presentation. However, CRT overexpression has been previously associated with the development of pancreatic and breast cancer. The import and retention signals of CRT in the endoplasmic reticulum (ER) can be used to overcome CRT overexpression. The present study describes the potent antitumor effect of a DNA vaccine encoding human papillomavirus type 16 E6 and E7 antigens flanked by ER import and retention signals (SP-E6E7m-KDEL). The effect of this vaccine was compared with that of E6 and E7 antigens fused to human full-length CRT (hCRT-E6E7m). In the present study, the effectiveness of SP-E6E7m-KDEL for inducing an interferon-γ antigen-specific, response and its therapeutic effect against tumors was demonstrated, which was as effective as immunization against those antigens fused to CRT. This simplified strategy, using ER import and retention signal peptides to direct antigens to this organelle, provides an efficient alternative to traditional vaccines and, more importantly, a safe and potent system to induce a therapeutic antitumor response.

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“…Several lines of evidence suggest that cell-mediated immunity is important in controlling both HPV infection and HPV-associated neoplasms [ 3 ]. Therefore, vaccines or immunotherapies targeting E7 protein may provide the opportunity to prevent and treat HPV-associated malignancies [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Toll-like receptors (TLRs) play an important role in the innate recognition of pathogen-associated molecular patterns (PAMPs) and initiation of immune responses in dendritic cells (DCs) [ 14 ]. TLR ligands have therefore emerged as potential vaccine adjuvants, particularly in the context of peptide, protein, and DNA vaccines [ 4 , 15 ]. Single TLR agonists are currently being developed and utilized for vaccination and tumor immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Combination of the toll like receptor agonist and α-Galactosylceramide as an efficient adjuvant for cancer vaccine

et al. 2016

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BackgroundDNA vaccines have emerged as an attractive approach for the generation of cytotoxic T lymphocytes (CTL). In our previous study, we found That Toll like receptor (TLR) ligands are promising candidates for the development of novel adjuvants for DNA vaccine. To improve the efficacy of DNA vaccine directed against human papillomavirus (HPV) tumors, we evaluated whether co-administration of a TLR4 ligand, monophosphoryl lipid A (MPL), and Natural Killer T Cell Ligand α-Galactosylceramide(α-GalCer) adjuvants with DNA vaccine would influence the anti-tumor efficacy of DNA vaccinations.MethodsWe investigated the effectiveness of α-GalCer and MPL combination as an adjuvant with an HPV-16 E7 DNA vaccine to enhance antitumor immune responses.ResultsBy using adjuvant combination for a DNA vaccine, we found that the levels of lymphocyte proliferation, CTL activity, IFN- γ, IL-4 and IL-12 responses, and tumor protection against TC-1 cells were significantly increased compared to the DNA vaccine with individual adjuvants.In addition, inhibition of IL-18 signaling during vaccination decreased IFN-γ responses and tumor protection, and that this inhibition suggested stimulatory role of IL-18 in adjuvant effects of α-GalCer and MPL combination.ConclusionThe strong adjuvanticity associated with α-GalCer/MPL combination may to be an important tool in the development of novel and strong cancer immunotherapy.

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DNA vaccine encoding HPV-16 E7 with mutation in L-Y-C-Y-E pRb-binding motif induces potent anti-tumor responses in mice

Cited by 22 publications

References 34 publications

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

DNA vaccine encoding human papillomavirus antigens flanked by a signal peptide and a KDEL sequence induces a potent therapeutic antitumor effect

Combination of the toll like receptor agonist and α-Galactosylceramide as an efficient adjuvant for cancer vaccine

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