RESUMO
Persistent human papillomavirus (HPV) infection is associated with multiple malignancies. Developing therapeutic vaccines to eliminate HPV-infected and malignant cells holds significant value. In this study, we introduced a lipid nanoparticle encapsulated mRNA vaccine expressing tHA-mE7-mE6. Mutations were introduced into E6 and E7 of HPV to eliminate their tumourigenicity. A truncated influenza haemagglutinin protein (tHA), which binds to the CD209 receptor on the surface of dendritic cells (DCs), was fused with mE7-mE6 in order to allow efficient uptake of antigen by antigen presenting cells. The tHA-mE7-mE6 (mRNA) showed higher therapeutic efficacy than mE7-mE6 (mRNA) in an E6 and E7+ tumour model. The treatment resulted in complete tumour regression and prevented tumour formation. Strong CD8+ T-cell immune response was induced, contributing to preventing and curing of E6 and E7+ tumour. Antigen-specific CD8+ T were found in spleens, peripheral blood and in tumours. In addition, the tumour infiltration of DC and NK cells were increased post therapy. In conclusion, this study described a therapeutic mRNA vaccine inducing strong anti-tumour immunity in peripheral and in tumour microenvironment, holding promising potential to treat HPV-induced cancer and to prevent cancer recurrence.
Assuntos
Vacinas Anticâncer , Células Dendríticas , Proteínas Oncogênicas Virais , Proteínas E7 de Papillomavirus , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Vacinas de mRNA , Animais , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Proteínas E7 de Papillomavirus/imunologia , Vacinas Anticâncer/imunologia , Proteínas Oncogênicas Virais/imunologia , Proteínas Oncogênicas Virais/genética , Vacinas contra Papillomavirus/imunologia , Células Dendríticas/imunologia , Humanos , Camundongos , Feminino , Linfócitos T CD8-Positivos/imunologia , Camundongos Endogâmicos C57BL , Nanopartículas , Células Apresentadoras de Antígenos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Células Matadoras Naturais/imunologia , Proteínas Repressoras/imunologia , Proteínas Repressoras/genética , Neoplasias/terapia , Neoplasias/imunologia , RNA Mensageiro/genética , Linhagem Celular Tumoral , LipossomosRESUMO
BACKGROUND: The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. METHODS: A case-control study was designed, comprising 150 people with PCOS and 300 controls. Logistic regression analysis was used to assess the association between the three missense mutations and PCOS. Linear regression analysis was used to assess the association between the three missense mutations and the homocysteine level. Mediation analysis was used to investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. RESULTS: Following adjustments and multiple rounds of testing, MTHFR A1298C was found to be significantly associated with PCOS in a dose-dependent manner (compared to AA, OR = 2.142 for AC & OR = 3.755 for CC; P < 0.001). MTRR A66G was nominally associated with PCOS. Mutations in MTHFR A1298C and MTRR A66G were significantly associated with the homocysteine level. Mediation analysis suggested the effect of MTHFR A1298C on PCOS was mediated by homocysteine. CONCLUSIONS: MTHFR A1298C and MTRR A66G were associated with PCOS, and MTHFR A1298C might affect the risk of PCOS by influencing the homocysteine level.