ABSTRACT
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.
Subject(s)
Cancer Vaccines , Dendritic Cells , Oncogene Proteins, Viral , Papillomavirus E7 Proteins , Papillomavirus Infections , Papillomavirus Vaccines , mRNA Vaccines , Animals , Papillomavirus Infections/immunology , Papillomavirus Infections/prevention & control , Papillomavirus E7 Proteins/immunology , Cancer Vaccines/immunology , Oncogene Proteins, Viral/immunology , Oncogene Proteins, Viral/genetics , Papillomavirus Vaccines/immunology , Dendritic Cells/immunology , Humans , Mice , Female , CD8-Positive T-Lymphocytes/immunology , Mice, Inbred C57BL , Nanoparticles , Antigen-Presenting Cells/immunology , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Killer Cells, Natural/immunology , Repressor Proteins/immunology , Repressor Proteins/genetics , Neoplasms/therapy , Neoplasms/immunology , RNA, Messenger/genetics , Cell Line, Tumor , LiposomesABSTRACT
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.
Subject(s)
Ferredoxin-NADP Reductase/genetics , Genetic Predisposition to Disease/genetics , Homocysteine/blood , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Mutation, Missense , Polycystic Ovary Syndrome/genetics , Adult , Asian People/genetics , Case-Control Studies , China , Female , Ferredoxin-NADP Reductase/metabolism , Gene Frequency , Genotype , Homocysteine/metabolism , Humans , Linkage Disequilibrium , Methylenetetrahydrofolate Reductase (NADPH2)/metabolism , Polycystic Ovary Syndrome/enzymology , Polycystic Ovary Syndrome/ethnology , Polymorphism, Single Nucleotide , Risk Factors , Young AdultABSTRACT
OBJECTIVE: This study aims to explore the causal relationship between Antibody-Mediated Immune Response (AIR) and female infertility using Mendelian randomization analysis, providing new targets and insights for treating female infertility. METHODS: Exposure data from a genome-wide association study (GWAS) involving 9724 participants provided information on 46 types of AIR. Outcome data were sourced from a large-scale meta-analysis of female infertility, which included 899 cases and 246,641 controls. Five different Mendelian randomization analysis methods were used to assess the genetic causal relationship between AIR and female infertility, with the inverse variance-weighted method as the primary approach. The robustness of the study results was evaluated through heterogeneity analysis, pleiotropy tests, and leave-one-out validation. Replication and meta-analysis were conducted using FinnGen data to further identify AIR. RESULTS: Through rigorous genetic variant screening, IVW, sensitivity analysis, replication, and meta-analysis, the results indicate that only seropositivity of anti-polyomavirus 2 IgG shows significant evidence of association with female infertility. The reverse MR analysis did not reveal a genetic causal association between female infertility and this antibody-influencing relationship. Sensitivity analysis showed no evidence of pleiotropy or heterogeneity. Replication and meta-analysis using FinnGen data further supported that only anti-polyomavirus 2 IgG seropositivity has a significant association with female infertility. CONCLUSION: Using Mendelian randomization analysis in two independent samples, this study presents evidence of a genetic association between anti-polyomavirus 2 IgG seropositivity and female infertility. These findings carry significant implications for the prevention and treatment of female infertility in clinical practice.