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1.
Pharmaceutics ; 16(7)2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39065637

RESUMO

Triple-negative breast cancer (TNBC) has been considered a huge clinical unmet need due to its aggressive progression and highly frequent metastasis. mRNA therapeutics supply a potential and versatile immunotherapy of oncology treatment. Here, we developed α-lactalbumin mRNA-lipid nanoparticles (α-LNP) as a potential therapeutical strategy for TNBC. The α-LNP induced the specific IgG antibodies and activated IFN γ-secreting-T cells in vivo. Additionally, the safety of α-LNP also had been demonstrated in vivo. When vaccinated prior to tumor implantation, α-LNP showed a preventive effect against 4T1 tumor growth and extended the survival of the tumor model by activating the memory immune responses. Furthermore, α-LNP administration in combination with surgical removal of neoplasm effectively inhibited the progression and metastasis in the TNBC model. Taken together, our results indicate that the α-LNP vaccine is a promising novel treatment for both therapeutics and prophylactics in TNBC.

2.
Oncoimmunology ; 13(1): 2373526, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948931

RESUMO

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.


Assuntos
Adjuvantes Imunológicos , Antígenos de Neoplasias , Vacinas Anticâncer , Células Dendríticas , Neoplasias da Próstata , RNA Mensageiro , Animais , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Antígenos de Neoplasias/imunologia , Camundongos , Células Dendríticas/imunologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Humanos , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Vacinas de mRNA , Linfócitos T CD8-Positivos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos
3.
iScience ; 27(5): 109818, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38766356

RESUMO

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

4.
J Adv Res ; 39: 225-235, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35777910

RESUMO

INTRODUCTION: The transcription factor NFIL3 exerts comprehensive effects on the immune system. Previous studies revealed that NFIL3 is related to the function and development of different immune cell subsets. Experimental autoimmune encephalomyelitis (EAE) is mediated by immune cells which results in inflammatory demyelination in the central nervous system (CNS). However, how NFIL3 affects EAE has not been thoroughly studied. OBJECTIVES: The current study aimed to investigate how NFIL3 affects EAE, especially the changes of T cells and dendritic cells as well as the crosstalk between them. METHODS: We used NFIL3-/- mice and C57BL/6J mice (wildtype) to establish MOG35-55-induced EAE. The clinical scores were recorded daily. The immune cells within and outside the CNS of EAE mice were analyzed by flow cytometry. Histology was used to evaluated the neuroinflammation and demyelination in the CNS. Besides, CD11c+ dendritic cells (DCs) were cocultured with T cells and the interplay was measured. RESULTS: At the peak of EAE, Th17 cells decreased within the CNS accompanying with lower clinical scores and milder neuroinflammation and demyelination in NFIL3 knockout EAE mice. Outside the CNS, PD-1 and ICOS on CD4+T cells increased, whereas Th2, Th9, CD8+CD103+T cells and GM-CSF+CD4+T cells decreased. Besides, the pro-inflammatory capacity of NFIL3-/- CD11c+ dendritic cells was impaired while the anti-inflammatory capacity was promoted. CONCLUSIONS: This study suggests that NFIL3 deficiency could alleviate MOG35-55-induced EAE through regulating different immune cell subsets, which is not only related with adaptive immunity and innate immunity, but also related with the cross-talk between them, especially CD4+ T cells and CD11c+ dendritic cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Encefalomielite Autoimune Experimental , Animais , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Células Th17/patologia
5.
JCI Insight ; 7(2)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34905507

RESUMO

Programmed death-1 homolog (PD-1H) is a coinhibitory molecule that negatively regulates T cell-mediated immune responses. In this study, we determined whether ablation of T cell-associated PD-1H could enhance adoptive T cell therapy in experimental tumor models. The expression of PD-1H is upregulated in activated and tumor-infiltrating CD8+ T cells. Activated CD8+ T cells from PD-1H-deficient (PD-1H-KO) mice exhibited increased cell proliferation, cytokine production, and antitumor activity in vitro. Adoptive transfer of PD-1H-KO CD8+ T cells resulted in the regression of established syngeneic mouse tumors. Similar results were obtained when PD-1H was ablated in T cells by CRISPR/Cas9-mediated gene silencing. Furthermore, ablation of PD-1H in CAR-T cells significantly improved their antitumor activity against human xenografts in vivo. Our results indicate that T cell-associated PD-1H could suppress immunity in the tumor microenvironment and that targeting PD-1H may improve T cell adoptive immunotherapy.


Assuntos
Transferência Adotiva/métodos , Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Proteínas de Membrana , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/biossíntese , Inativação Gênica , Marcação de Genes/métodos , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/imunologia , Camundongos , Neoplasias Experimentais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Ther ; 28(6): 1518-1532, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32304668

RESUMO

Osteoporosis is a disease in which the density and quality of bone are reduced, causing bones to become weak and so brittle that a fall or even mild stresses can cause a fracture. Current drug treatment consists mainly of antiresorptive agents that are unable to stimulate new bone formation. Our recent studies have defined a critical role of gingiva-derived mesenchymal stem cells (GMSCs) in attenuating autoimmune arthritis through inhibition of osteoclast formation and activities, but it remains to be ruled out whether the administration of GMSCs to patients with osteoporosis could also regulate osteoblasts and eventually affect bone formation and protection. With the use of an ovariectomized mouse model, we here demonstrated that adoptive transfer of GMSCs regulated the balance of osteoclasts and osteoblasts, eventually contributing to dynamic bone formation. Validation by RNA sequencing (RNA-seq), single-cell sequencing, revealed a unique population of CD39+ GMSC that plays an important role in promoting bone formation. We further demonstrated that CD39 produced from GMSC exerted its osteogenic capacity through the Wnt/ß-catenin pathway. Our results not only establish a previously unidentified role and mechanism of GMSC for bone promotion but also a potential therapeutic target for management of patients with osteoporosis and other bone loss conditions.


Assuntos
Apirase/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/etiologia , Osteoporose/metabolismo , Via de Sinalização Wnt , Animais , Remodelação Óssea/genética , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Feminino , Gengiva/citologia , Humanos , Imunomodulação , Modelos Biológicos , Osteogênese
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