Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells
T cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8+ T cells, the application of CD4+ T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4+ TCR-Ts h...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.939940/full |
| _version_ | 1811218670152581120 |
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| author | Yanling Liang Yanling Liang Qumiao Xu Songming Liu Jie Li Jie Li Fei Wang Ziyi Li Lijuan Liao Yuting Lu Yijian Li Feng Mu Hai-Xi Sun Hai-Xi Sun Hai-Xi Sun Linnan Zhu Linnan Zhu Linnan Zhu |
| author_facet | Yanling Liang Yanling Liang Qumiao Xu Songming Liu Jie Li Jie Li Fei Wang Ziyi Li Lijuan Liao Yuting Lu Yijian Li Feng Mu Hai-Xi Sun Hai-Xi Sun Hai-Xi Sun Linnan Zhu Linnan Zhu Linnan Zhu |
| author_sort | Yanling Liang |
| collection | DOAJ |
| description | T cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8+ T cells, the application of CD4+ T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4+ TCR-Ts have not been fully revealed. In this study, we obtained an MHC class I-restricted MART-127-35-specific TCR sequence based on the single-cell V(D)J sequencing technology, and constructed MART-127-35-specific CD4+ TCR-Ts and CD8+ TCR-Ts. The antitumor effects of CD4+ TCR-Ts were comparable to those of CD8+ TCR-Ts in vitro and in vivo. To delineate the killing mechanisms of cytotoxic CD4+ TCR-Ts, we performed single-cell RNA sequencing and found that classical granule-dependent and independent cytolytic pathways were commonly used in CD4+ and CD8+ TCR-Ts, while high expression of LTA and various costimulatory receptors were unique features for cytotoxic CD4+ TCR-Ts. Further signaling pathway analysis revealed that transcription factors Runx3 and Blimp1/Tbx21 were crucial for the development and killing function of cytotoxic CD4+ T cells. Taken together, we report the antitumor effects and multifaceted killing mechanisms of CD4+ TCR-Ts, and also indicate that MHC class I-restricted CD4+ TCR-Ts could serve as potential adoptive T cell therapies. |
| first_indexed | 2024-04-12T07:13:18Z |
| format | Article |
| id | doaj.art-f785a6c4974948f2998e7c82d77f4eec |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T07:13:18Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f785a6c4974948f2998e7c82d77f4eec2022-12-22T03:42:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.939940939940Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T CellsYanling Liang0Yanling Liang1Qumiao Xu2Songming Liu3Jie Li4Jie Li5Fei Wang6Ziyi Li7Lijuan Liao8Yuting Lu9Yijian Li10Feng Mu11Hai-Xi Sun12Hai-Xi Sun13Hai-Xi Sun14Linnan Zhu15Linnan Zhu16Linnan Zhu17College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI), Shenzhen, ChinaCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBeijing Genomics Institute (BGI)-Beijing, Beijing, ChinaBeijing Genomics Institute (BGI)-Shenzhen, Shenzhen, ChinaBiomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, ChinaInstitute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, ChinaT cell receptor-engineered T cells (TCR-Ts) have emerged as potent cancer immunotherapies. While most research focused on classical cytotoxic CD8+ T cells, the application of CD4+ T cells in adoptive T cell therapy has gained much interest recently. However, the cytotoxic mechanisms of CD4+ TCR-Ts have not been fully revealed. In this study, we obtained an MHC class I-restricted MART-127-35-specific TCR sequence based on the single-cell V(D)J sequencing technology, and constructed MART-127-35-specific CD4+ TCR-Ts and CD8+ TCR-Ts. The antitumor effects of CD4+ TCR-Ts were comparable to those of CD8+ TCR-Ts in vitro and in vivo. To delineate the killing mechanisms of cytotoxic CD4+ TCR-Ts, we performed single-cell RNA sequencing and found that classical granule-dependent and independent cytolytic pathways were commonly used in CD4+ and CD8+ TCR-Ts, while high expression of LTA and various costimulatory receptors were unique features for cytotoxic CD4+ TCR-Ts. Further signaling pathway analysis revealed that transcription factors Runx3 and Blimp1/Tbx21 were crucial for the development and killing function of cytotoxic CD4+ T cells. Taken together, we report the antitumor effects and multifaceted killing mechanisms of CD4+ TCR-Ts, and also indicate that MHC class I-restricted CD4+ TCR-Ts could serve as potential adoptive T cell therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.939940/fullcytotoxic CD4+ TTCR-Tsingle-cell RNA sequencingadoptive T cell therapyLTA |
| spellingShingle | Yanling Liang Yanling Liang Qumiao Xu Songming Liu Jie Li Jie Li Fei Wang Ziyi Li Lijuan Liao Yuting Lu Yijian Li Feng Mu Hai-Xi Sun Hai-Xi Sun Hai-Xi Sun Linnan Zhu Linnan Zhu Linnan Zhu Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells Frontiers in Immunology cytotoxic CD4+ T TCR-T single-cell RNA sequencing adoptive T cell therapy LTA |
| title | Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells |
| title_full | Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells |
| title_fullStr | Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells |
| title_full_unstemmed | Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells |
| title_short | Single-Cell Transcriptomics Reveals Killing Mechanisms of Antitumor Cytotoxic CD4+ TCR-T Cells |
| title_sort | single cell transcriptomics reveals killing mechanisms of antitumor cytotoxic cd4 tcr t cells |
| topic | cytotoxic CD4+ T TCR-T single-cell RNA sequencing adoptive T cell therapy LTA |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.939940/full |
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