Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers
An immunosuppressive state is regulated by various factors in the tumor microenvironment (TME), including, but not limited to, metabolic plasticity of immunosuppressive cells and cytokines secreted by these cells. We used single‐cell RNA‐sequencing (scRNA‐seq) data and applied single‐cell flux estim...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13373 |
| _version_ | 1797856173055016960 |
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| author | Jinfen Wei Wenqi Yu Juanzhi Chen Guanda Huang Lingjie Zhang Zixi Chen Meiling Hu Xiaocheng Gong Hongli Du |
| author_facet | Jinfen Wei Wenqi Yu Juanzhi Chen Guanda Huang Lingjie Zhang Zixi Chen Meiling Hu Xiaocheng Gong Hongli Du |
| author_sort | Jinfen Wei |
| collection | DOAJ |
| description | An immunosuppressive state is regulated by various factors in the tumor microenvironment (TME), including, but not limited to, metabolic plasticity of immunosuppressive cells and cytokines secreted by these cells. We used single‐cell RNA‐sequencing (scRNA‐seq) data and applied single‐cell flux estimation analysis to characterize the link between metabolism and cellular function within the hypoxic TME of colorectal (CRC) and lung cancer. In terms of metabolic heterogeneity, we found myeloid cells potentially inclined to accumulate glutamine but tumor cells inclined to accumulate glutamate. In particular, we uncovered a tumor‐associated macrophage (TAM) subpopulation, APOE+CTSZ+TAM, that was present in high proportions in tumor samples and exhibited immunosuppressive characteristics through upregulating the expression of anti‐inflammatory genes. The proportion of APOE+CTSZ+TAM and regulatory T cells (Treg) were positively correlated across CRC scRNA‐seq samples. APOE+CTSZ+TAM potentially interacted with Treg via CXCL16–CCR6 signals, as seen by ligand–receptor interactions analysis. Notably, glutamate‐to‐glutamine metabolic flux score and glutamine synthetase (GLUL) expression were uniquely higher in APOE+CTSZ+TAM, compared with other cell types within the TME. GLUL expression in macrophages was positively correlated with anti‐inflammatory score and was higher in high‐grade and invasive tumor samples. Moreover, spatial transcriptome and multiplex immunofluorescence staining of samples showed that APOE+CTSZ+TAM and Treg potentially colocalized in the tissue sections from CRC clinical samples. These results highlight the specific role and metabolic characteristic of the APOE+CTSZ+TAM subpopulation and provide a new perspective for macrophage subcluster‐targeted therapeutic interventions or metabolic checkpoint‐based cancer therapies. |
| first_indexed | 2024-04-09T20:36:04Z |
| format | Article |
| id | doaj.art-c2e673cfbbdd44af85e603b637c83f8b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-09T20:36:04Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-c2e673cfbbdd44af85e603b637c83f8b2023-03-30T08:40:48ZengWileyMolecular Oncology1574-78911878-02612023-04-0117461162810.1002/1878-0261.13373Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancersJinfen Wei0Wenqi Yu1Juanzhi Chen2Guanda Huang3Lingjie Zhang4Zixi Chen5Meiling Hu6Xiaocheng Gong7Hongli Du8School of Biology and Biological Engineering South China University of Technology Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaDepartment of Pathology, School of Basic Medical Sciences Southern Medical University Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaDepartment of Pathology, School of Basic Medical Sciences Southern Medical University Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaSchool of Biology and Biological Engineering South China University of Technology Guangzhou ChinaAn immunosuppressive state is regulated by various factors in the tumor microenvironment (TME), including, but not limited to, metabolic plasticity of immunosuppressive cells and cytokines secreted by these cells. We used single‐cell RNA‐sequencing (scRNA‐seq) data and applied single‐cell flux estimation analysis to characterize the link between metabolism and cellular function within the hypoxic TME of colorectal (CRC) and lung cancer. In terms of metabolic heterogeneity, we found myeloid cells potentially inclined to accumulate glutamine but tumor cells inclined to accumulate glutamate. In particular, we uncovered a tumor‐associated macrophage (TAM) subpopulation, APOE+CTSZ+TAM, that was present in high proportions in tumor samples and exhibited immunosuppressive characteristics through upregulating the expression of anti‐inflammatory genes. The proportion of APOE+CTSZ+TAM and regulatory T cells (Treg) were positively correlated across CRC scRNA‐seq samples. APOE+CTSZ+TAM potentially interacted with Treg via CXCL16–CCR6 signals, as seen by ligand–receptor interactions analysis. Notably, glutamate‐to‐glutamine metabolic flux score and glutamine synthetase (GLUL) expression were uniquely higher in APOE+CTSZ+TAM, compared with other cell types within the TME. GLUL expression in macrophages was positively correlated with anti‐inflammatory score and was higher in high‐grade and invasive tumor samples. Moreover, spatial transcriptome and multiplex immunofluorescence staining of samples showed that APOE+CTSZ+TAM and Treg potentially colocalized in the tissue sections from CRC clinical samples. These results highlight the specific role and metabolic characteristic of the APOE+CTSZ+TAM subpopulation and provide a new perspective for macrophage subcluster‐targeted therapeutic interventions or metabolic checkpoint‐based cancer therapies.https://doi.org/10.1002/1878-0261.13373colorectal cancerGLULimmunosuppressive microenvironmentmetabolismsingle‐cell and spatial RNA‐seqtumor‐associated macrophages |
| spellingShingle | Jinfen Wei Wenqi Yu Juanzhi Chen Guanda Huang Lingjie Zhang Zixi Chen Meiling Hu Xiaocheng Gong Hongli Du Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers Molecular Oncology colorectal cancer GLUL immunosuppressive microenvironment metabolism single‐cell and spatial RNA‐seq tumor‐associated macrophages |
| title | Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers |
| title_full | Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers |
| title_fullStr | Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers |
| title_full_unstemmed | Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers |
| title_short | Single‐cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers |
| title_sort | single cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of apoe ctsz tam in cancers |
| topic | colorectal cancer GLUL immunosuppressive microenvironment metabolism single‐cell and spatial RNA‐seq tumor‐associated macrophages |
| url | https://doi.org/10.1002/1878-0261.13373 |
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