Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma
Background Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.Metho...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010183.full |
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| author | Lijuan Wang Qian He Weijun Qin Xiyu Song Yumeng Zhu Wenwen Geng Jianhua Jiao Hongjiao Liu Ruo Chen Xiuxuan Sun Jiejie Geng Zhinan Chen |
| author_facet | Lijuan Wang Qian He Weijun Qin Xiyu Song Yumeng Zhu Wenwen Geng Jianhua Jiao Hongjiao Liu Ruo Chen Xiuxuan Sun Jiejie Geng Zhinan Chen |
| author_sort | Lijuan Wang |
| collection | DOAJ |
| description | Background Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.Methods To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays.Results In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transitionhigh clusters, metastatic clusters and proximal tubulehigh clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with MRC1+FOLR2+ tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β+ Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway.Conclusions We demonstrated a novel cancer-promoting Treg cell subset and its interactions with MRC1+FOLR2+TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC. |
| format | Article |
| id | doaj-art-3d718eb1bbf543ad8defda2f41877d1a |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3d718eb1bbf543ad8defda2f41877d1a2025-01-27T08:10:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010183Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinomaLijuan Wang0Qian He1Weijun Qin2Xiyu Song3Yumeng Zhu4Wenwen Geng5Jianhua Jiao6Hongjiao Liu7Ruo Chen8Xiuxuan Sun9Jiejie Geng10Zhinan Chen11National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Urology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaDepartment of Breast Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, ChinaXijing Innovation Research Institute, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi`an, Shaanxi, ChinaBackground Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.Methods To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays.Results In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transitionhigh clusters, metastatic clusters and proximal tubulehigh clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with MRC1+FOLR2+ tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β+ Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway.Conclusions We demonstrated a novel cancer-promoting Treg cell subset and its interactions with MRC1+FOLR2+TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC.https://jitc.bmj.com/content/13/1/e010183.full |
| spellingShingle | Lijuan Wang Qian He Weijun Qin Xiyu Song Yumeng Zhu Wenwen Geng Jianhua Jiao Hongjiao Liu Ruo Chen Xiuxuan Sun Jiejie Geng Zhinan Chen Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma Journal for ImmunoTherapy of Cancer |
| title | Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma |
| title_full | Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma |
| title_fullStr | Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma |
| title_full_unstemmed | Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma |
| title_short | Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma |
| title_sort | spatial and single cell transcriptomics reveal cellular heterogeneity and a novel cancer promoting treg cell subset in human clear cell renal cell carcinoma |
| url | https://jitc.bmj.com/content/13/1/e010183.full |
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