Vaccination with human papillomavirus-18 E1 protein plus α-galactosyl-ceramide induces CD8+ cytotoxic response and impairs the growth of E1-expressing tumors

Amador-Molina, Alfredo; Trejo-Moreno, Cesar; Romero-Rodríguez, Dámaris P.; Sada‐Ovalle, Isabel; Pérez-Cárdenas, Enrique; Lamoyi, Edmundo; Moreno, José; Lizano, Marcela

doi:10.1016/j.vaccine.2018.12.036

Cited by 11 publications

(8 citation statements)

References 44 publications

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“…Mart Ustav (University of Tartu, Estonia). HPV18 HA tagged E1 expressing plasmid was previously described by our group 59 . The pCA vector was used as transfection control.…”

Section: Methodsmentioning

confidence: 99%

The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response

Castro-Muñoz

Manzo-Merino

Muñoz-Bello

et al. 2019

Sci Rep

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The Human Papillomavirus (HPV) E1 protein is the only viral protein with enzymatic activity. The main known function of this protein is the regulation of the viral DNA replication. Nevertheless, it has been demonstrated that the ablation of HPV18 E1 mRNA in HeLa cells promotes a deregulation of several genes, particularly those involved in host defense mechanisms against viral infections; however, the specific contribution of E1 protein in HPV-independent context has not been studied. The aim of this work was to determine the effect of the HPV E1 protein in the regulation of cellular gene expression profiles evaluated through RNA-seq. We found that E1 proteins from HPV16 and 18 induced an overexpression of different set of genes associated with proliferation and differentiation processes, as well as downregulation of immune response genes, including IFNβ1 and IFNλ1 and Interferon-stimulated gene (ISG), which are important components involved in the antiviral immune response. Together, our results indicate that HR-(High-Risk) and LR-(Low-Risk) HPV E1 proteins play an important role in inhibiting the anti-viral immune response.

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“…Mart Ustav (University of Tartu, Estonia). HPV18 HA tagged E1 expressing plasmid was previously described by our group 59 . The pCA vector was used as transfection control.…”

Section: Methodsmentioning

confidence: 99%

The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response

Castro-Muñoz

Manzo-Merino

Muñoz-Bello

et al. 2019

Sci Rep

Self Cite

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“…Beyond SARS-CoV-2, sphingomyelinase inhibitors have the potential to inhibit viral entry and dissemination in a broader range of viruses (summarized in Table 2 and Table 3 ). Additionally, α-GalCer harbors great potential as an adjuvant and immune modulator in viral infections [ 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 223 , 224 , 225 , 226 , 227 ]. Future studies will have to carefully consider the effect of sphingolipid modulation for the respective virus studied, however, as even the same agent can have opposing biological effects for different viruses [ 55 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…This rationale underlies a plethora of studies investigating the use of α-GalCer as a vaccine adjuvant. So far, α-GalCer has been tested as an adjuvant for human papillomavirus (HPV) [ 203 ], IAV [ 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 ], HSV-2 [ 214 , 215 ], HIV-1 [ 216 , 217 ] and human metapneumovirus [ 218 ] vaccines.…”

Section: Viral Immune Evasion and Immune Modulationmentioning

confidence: 99%

Ceramide and Related Molecules in Viral Infections

Beckmann

Becker

2021

IJMS

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Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.

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“…Comparing with most tumor models, TC1 cell lines can concurrently metastasize from the primary tumor in the cervical gland to other sites such as blood, liver, brain, lung, bone and lymph nodes just, similar to human cervical cancer [ 4 ]. Recent studies show that alpha galactosyl ceramide, glycosphingolipid derived from a sea sponge known as a combination with anti-metastasis, antitumor and immune system stimulates the capability of α-GalCer and increase the proliferation and activity of NK and NKT cells and production of cytokines [ 5 ]. Combination therapy with Fluorouracil (5-FU) and alpha galactosyl ceramide in mouse model of liver tumor increased the expression of NK activating molecules on cancer cells, which had a synergistic antitumor effect on liver tumors [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Combined extract of heated TC1, a heat-killed preparation of Lactobacillus casei and alpha-galactosyl ceramide in a mouse model of cervical cancer

Haghighi

Yazdani

Farzanehpour

et al. 2022

Infect Agents Cancer

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Background Nowadays, cancer is the leading cause of death among threats to humanity, necessitating prompt action and preparation. Cervical cancer is one of the most common cancers in women and is currently treated with surgery, radiation, chemotherapy, and immunotherapy, among other treatments. Current oncology approaches focused on the simultaneous development of safe and effective cancer multi-agent therapies. The present study aimed to evaluate the effects of a combined extracts of heated TC1, a heat-killed preparation of Lactobacilluscasei, and alpha-galactosyl ceramide (α-GalCer) in a mouse model of cervical cancer. Material and methods Cervical cancer in the mouse model was prepared by TC1 cells subcutaneous injection into the left flank of female C57BL/6 mouse aged 6–8 weeks (n = 80). After the appearance of the palpable tumor, the mice with cervical cancer were randomly devoted to 8 (ten-member) groups. The mice in some groups were treated with PBS, TC1 cell extract, L. casei extract, α-GalCer, and a combination of the mentioned treatments. Then, they were evaluated the splenocytes proliferation, lactate dehydrogenase production and nitric oxide. Moreover, IL-4, IFN-γ, and TGF-β cytokine levels of splenocytes supernatant the mice were measured. In all evaluations, a statistical difference of less than 0.05 (P ˂ 0.05) was considered as a significant level. Result The findings revealed that the combination therapy group (heated TC1 cell and L. casei extracts with α-GalCer) significantly increases the splenocytes proliferation (MTT) (0.358 ± 0.04 OD), LDH production (45.9 ± 2.3 U/L), NO rate (38.4 ± 2.8 µM), and IFN-γ cytokine level (46.6 ± 3.7 pg/ml) (P < 0.05). Also, observes a significantly reduces the production of IL-4 (11.6 ± 2.5 pg/ml) and TGF-β cytokines levels (7.8 ± 2.5 pg/ml) (P < 0.05) in comparison to the control group. Conclusion The study showed that combination therapy of L. casei and α-GalCer is an efficient treatment for cervical cancer in the mouse model.

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Vaccination with human papillomavirus-18 E1 protein plus α-galactosyl-ceramide induces CD8+ cytotoxic response and impairs the growth of E1-expressing tumors

Cited by 11 publications

References 44 publications

The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response

The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response

Ceramide and Related Molecules in Viral Infections

Combined extract of heated TC1, a heat-killed preparation of Lactobacillus casei and alpha-galactosyl ceramide in a mouse model of cervical cancer

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