bims-maitce 2024-11-17 papers

Issue of 2024–11–17
three papers selected by
Andy E. Hogan, Maynooth University

Int J Nanomedicine. 2024 ;19 11479-11497

Nasal mRNA Nanovaccine with Key Activators of Dendritic and MAIT Cells for Effective Against Lung Tumor Metastasis in Mice Model.

Ang Li, Xushan Cai, Dong Li, Yimin Yu, Chengyu Liu, Jie Shen, Jiaqi You, Jianou Qiao, Feng Wang.

Background: Lung metastasis is a leading cause of cancer-related death. mRNA-based cancer vaccines have been demonstrated to be effective at inhibiting tumor growth. Intranasal immunization has emerged as a more effective method of inducing local immune responses against cancer cells in the lungs.
Methods: An innovative layered double hydroxide- and 5-OP-RU-based mRNA nanovaccine (Mg/Al LDH-5-OP-RU/mRNA) was synthesized via coprecipitation. The particle size distribution and zeta potential were measured, and the nanovaccine was observed by transmission electron microscopy. The functions and properties of the nanovaccine were evaluated via an mRNA-targeted delivery assay and measurement of dendritic cell (DC) and mucosa-associated invariant T (MAIT) cell maturation and activation. In addition, the cytotoxicity, antigen-specific T cell activation, cytokines, protective ability, and therapeutic ability of the nanovaccine were assessed in a mouse tumor model. Further, the immune cell composition was evaluated in tumors.
Results: The Mg/Al LDH-5-OP-RU/mRNA nanovaccine was efficiently delivered into lung-draining mediastinal lymph nodes (MLNs), and it activated dendritic cells (DCs) and mucosa-associated invariant T (MAIT) cells after intranasal administration. Moreover, the optimized dual-activating mRNA nanovaccine efficiently transfected DC cells and expressed antigen proteins in DC cells. An HPV-associated tumor model revealed that the intranasal delivery of the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine significantly prevented the lung metastasis of tumors and had a therapeutic effect on established metastatic tumor nodules in the lungs. Mechanistically, the enhanced activation of DC and MAIT cells induced by the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine increased the production of immune-stimulating cytokines and decreased the secretion of immunosuppressive cytokines, which led to the expansion and activation of memory T cells targeting the E7 antigen, a reduction in the population of neutrophils, and differentiation of tumor -associated macrophages to the M1 phenotype in the lungs.
Conclusion: These results highlight the potential of the innovative nasal mRNA nanovaccine for both preventing and treating tumor metastasis in the lungs.

Keywords: 5-OP-RU; Mucosa-associated invariant T cells; dendritic cells; layered double hydroxide; lung metastasis; mRNA nanovaccine

DOI: https://doi.org/10.2147/IJN.S479741

Front Immunol. 2024 ;15 1436114

A distinct immune landscape in anti-synthetase syndrome profiled by a single-cell genomic study.

Objectives: The objective of this study was to profile the transcriptional profiles of peripheral blood mononuclear cells (PBMCs) and their immune repertoires affected by anti-synthetase syndrome (ASS) at the single-cell level.
Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of PBMCs and bulk RNA sequencing for patients with ASS (N=3) and patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM, N=3) along with healthy controls (HCs, N=4). As ASS and MDA5+ DM have similar organ involvements, MDA5+ DM was used as a disease control. The immune repertoire was constructed by reusing the same scRNA-seq datasets. Importantly, flow cytometry was performed to verify the results from the scRNA-seq analysis.
Results: After meticulous annotation of PBMCs, we noticed a significant decrease in the proportion of mucosal-associated invariant T (MAIT) cells in ASS patients compared to HCs, while there was a notable increase in the proportion of proliferative NKT cells. Compared with MDA5+ DM patients, in their PBMCs ASS patients presented substantial enrichment of interferon pathways, which were primarily mediated by IFN-II, and displayed a weak immune response. Furthermore, ASS patients exhibited more pronounced metabolic abnormalities, which may in turn affect oxidative phosphorylation pathways. Monocytes from ASS patients appear to play a crucial role as receptive signaling cells for the TNF pathway. Immunophenotyping analysis of PBMCs from ASS patients revealed an increasing trend for the clone type CQQSYSTPWTF.
Conclusion: Using single-cell genomic datasets of ASS PBMCs, we revealed a distinctive profile in the immune system of individuals with ASS, compared to that with MDA5+ DM or healthy controls.

Keywords: IFN-II; anti-synthetase syndrome (ASS); auto-immune diseases; mucosal-associated invariant T (MAIT) cell; single-cell RNA sequencing (scRNA-seq)

DOI: https://doi.org/10.3389/fimmu.2024.1436114

Br J Dermatol. 2024 Nov 12. pii: ljae442. [Epub ahead of print]

The roles of IL-17A and IL-17F in hidradenitis suppurativa pathogenesis: evidence from human in vitro preclinical experiments and clinical samples.

Joseph Rastrick, Hannah Edwards, Alex S Ferecskó, Gaëlle Le Friec, Avneet Manghera, Matthew Page, Stevan Shaw.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines IL-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A.
OBJECTIVES: To further investigate the roles of IL-17A and IL-17F in HS pathogenesis.
METHODS: RNA sequencing was conducted on skin biopsies taken at baseline and after treatment at Week 12 of the phase 2 proof of concept study of bimekizumab in patients with moderate to severe HS. Differentially expressed genes were identified between baseline lesional and non-lesional samples and between lesional samples before and after bimekizumab treatment to describe molecular disease mechanisms and treatment effect.Human hair follicular keratinocytes (HHFK) were cultured and treated with the supernatant of stimulated Th17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNA sequencing (RNAseq). Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays.
RESULTS: RNAseq revealed that the most prominently upregulated genes within HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. Extent of reduction in gene expression was dependent on HiSCR50 fulfilment. In vitro, dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs compared to IL-17A or IL-17F inhibition alone. In situ hybridisation revealed IL-17A and IL-17F producing cells in HS lesions can lack IL-23R and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1R1. IL-1β, IL-17A and IL-17F expressing cells were found to be co-localised in HS lesions.
CONCLUSIONS: These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1β may partly explain the high expression of IL-17F in lesional HS tissue.

DOI: https://doi.org/10.1093/bjd/ljae442