INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma
Abstract Transcriptomic and metabolic profiles of tumor cells and stromal cells in oral squamous cell carcinoma (OSCC)-derived from oral submucosal fibrosis (OSF) (ODSCC) have been reported. However, the complex intercellular regulatory network within the tumor immunosuppressive microenvironment (TI...
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2025-05-01
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| Online Access: | https://doi.org/10.1186/s12885-025-14261-2 |
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| author | Simin Zhao Yu Zhang Xiaoqin Meng Ye Wang Yahui Li Hao Li Xingyu Zhao Pishan Yang Shaopeng Liu Chengzhe Yang |
| author_facet | Simin Zhao Yu Zhang Xiaoqin Meng Ye Wang Yahui Li Hao Li Xingyu Zhao Pishan Yang Shaopeng Liu Chengzhe Yang |
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| description | Abstract Transcriptomic and metabolic profiles of tumor cells and stromal cells in oral squamous cell carcinoma (OSCC)-derived from oral submucosal fibrosis (OSF) (ODSCC) have been reported. However, the complex intercellular regulatory network within the tumor immunosuppressive microenvironment (TISME) in ODSCC remains poorly elucidated. Here, we utilized single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data from GEO database and multiple immunofluorescence staining (mIF) to reveal distinctive TISME of ODSCC. Results found that compared to OSCC without OSF history (NODSCC), OSCC derived from OSF (ODSCC) showed a significant increase in exhausted CD8+T and Treg cells (Ro/e > 1, p < 0.05) and a decrease in cytotoxic T (CTL) (Ro/e < 1). ODSCC enriched in more Inhibin subunit beta A+ Macrophages (INHBA+Mac) and Proinflammatory Cancer-associated Fibroblast (iCAF) versus NODSCC. INHBA+Mac possessed strongest immune-suppressive functions, evidenced by highest immune checkpoint scores, lowest MHC scores and highest expression of SPP1 among macrophages. Moreover, INHBA+Mac in ODSCC presented stronger immune-suppressive functions than that in NODSCC. iCAF differentially highly expressed INHBA and enriched in immune-related pathways and collagen/ECM pathways across CAF subsets, and possessed stronger immune-suppressive functions, as shown by up-regulated gene expression of TDO2, IDO1 and DUSP4 in ODSCC versus in NODSCC. Furthermore, INHBA expression was higher in ODSCC than in NODSCC (p < 0.01). The classic OSF-inducing molecule arecoline significantly increases the expression of INHBA (p < 0.0001) in vitro experiments stimulating THP-1 cells. ST analysis revealed a close co-location of INHBA+Mac, iCAF and Treg and SpaGene identified INHBA-ACVR1/ACVR2A/ACVR2B interaction regions overlapping with distribution of three types of cells. Collectively, ODSCC shows a more severe TISME and potentially poorer sensitivity to immunotherapy than NODSCC. The increased INHBA+Mac and iCAF in ODSCC are associated with the observed more severe TISME. The upregulated INHBA in ODSCC and its interaction with INHBA-ACVR1/ACVR2A/ACVR2B may mediate the modulation effect of INHBA+ Mac and iCAF on Treg differentiation and functionality. |
| format | Article |
| id | doaj-art-4631d8a9523740c88db3a81aed5764f7 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-4631d8a9523740c88db3a81aed5764f72025-08-20T01:51:39ZengBMCBMC Cancer1471-24072025-05-0125111910.1186/s12885-025-14261-2INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinomaSimin Zhao0Yu Zhang1Xiaoqin Meng2Ye Wang3Yahui Li4Hao Li5Xingyu Zhao6Pishan Yang7Shaopeng Liu8Chengzhe Yang9Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversityDepartment of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversityDepartment of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversityDepartment of Stomatology, Shandong Provincial Hospital, Shandong Provincial Hospital Affiliated to Shandong First Medical University &Department of Stomatology, Shandong UniversityDepartment of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversityDepartment of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversitySchool and Hospital of Stomatology, Cheeloo College of Medicine, Shandong UniversityDepartment of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Stomatology, Shandong Provincial Hospital, Shandong Provincial Hospital Affiliated to Shandong First Medical University &Department of Stomatology, Shandong UniversityDepartment of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong UniversityAbstract Transcriptomic and metabolic profiles of tumor cells and stromal cells in oral squamous cell carcinoma (OSCC)-derived from oral submucosal fibrosis (OSF) (ODSCC) have been reported. However, the complex intercellular regulatory network within the tumor immunosuppressive microenvironment (TISME) in ODSCC remains poorly elucidated. Here, we utilized single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data from GEO database and multiple immunofluorescence staining (mIF) to reveal distinctive TISME of ODSCC. Results found that compared to OSCC without OSF history (NODSCC), OSCC derived from OSF (ODSCC) showed a significant increase in exhausted CD8+T and Treg cells (Ro/e > 1, p < 0.05) and a decrease in cytotoxic T (CTL) (Ro/e < 1). ODSCC enriched in more Inhibin subunit beta A+ Macrophages (INHBA+Mac) and Proinflammatory Cancer-associated Fibroblast (iCAF) versus NODSCC. INHBA+Mac possessed strongest immune-suppressive functions, evidenced by highest immune checkpoint scores, lowest MHC scores and highest expression of SPP1 among macrophages. Moreover, INHBA+Mac in ODSCC presented stronger immune-suppressive functions than that in NODSCC. iCAF differentially highly expressed INHBA and enriched in immune-related pathways and collagen/ECM pathways across CAF subsets, and possessed stronger immune-suppressive functions, as shown by up-regulated gene expression of TDO2, IDO1 and DUSP4 in ODSCC versus in NODSCC. Furthermore, INHBA expression was higher in ODSCC than in NODSCC (p < 0.01). The classic OSF-inducing molecule arecoline significantly increases the expression of INHBA (p < 0.0001) in vitro experiments stimulating THP-1 cells. ST analysis revealed a close co-location of INHBA+Mac, iCAF and Treg and SpaGene identified INHBA-ACVR1/ACVR2A/ACVR2B interaction regions overlapping with distribution of three types of cells. Collectively, ODSCC shows a more severe TISME and potentially poorer sensitivity to immunotherapy than NODSCC. The increased INHBA+Mac and iCAF in ODSCC are associated with the observed more severe TISME. The upregulated INHBA in ODSCC and its interaction with INHBA-ACVR1/ACVR2A/ACVR2B may mediate the modulation effect of INHBA+ Mac and iCAF on Treg differentiation and functionality.https://doi.org/10.1186/s12885-025-14261-2Oral squamous cell carcinomaSubmucosal fibrosisInhibin subunit beta AImmunosuppressive microenvironmentMacrophage |
| spellingShingle | Simin Zhao Yu Zhang Xiaoqin Meng Ye Wang Yahui Li Hao Li Xingyu Zhao Pishan Yang Shaopeng Liu Chengzhe Yang INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma BMC Cancer Oral squamous cell carcinoma Submucosal fibrosis Inhibin subunit beta A Immunosuppressive microenvironment Macrophage |
| title | INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma |
| title_full | INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma |
| title_fullStr | INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma |
| title_full_unstemmed | INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma |
| title_short | INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma |
| title_sort | inhba macrophages and pro inflammatory cafs are associated with distinctive immunosuppressive tumor microenvironment in submucous fibrosis derived oral squamous cell carcinoma |
| topic | Oral squamous cell carcinoma Submucosal fibrosis Inhibin subunit beta A Immunosuppressive microenvironment Macrophage |
| url | https://doi.org/10.1186/s12885-025-14261-2 |
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