Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis
Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy r...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/171559 |
| _version_ | 1811687270682460160 |
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| author | Zhou, Jingying Wang, Huanyu Shu, Ting Wang, Jing Yang, Weiqin Li, Jingqing Ding, Lipeng Liu, Man Sun, Hanyong Wong, John Lai, Paul Bo-San Tsang, Shun-Wa Ward, Simon E. Chow, King-Lau Sung, Joseph Jao Yiu Cheng, Alfred Sze-Lok |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Zhou, Jingying Wang, Huanyu Shu, Ting Wang, Jing Yang, Weiqin Li, Jingqing Ding, Lipeng Liu, Man Sun, Hanyong Wong, John Lai, Paul Bo-San Tsang, Shun-Wa Ward, Simon E. Chow, King-Lau Sung, Joseph Jao Yiu Cheng, Alfred Sze-Lok |
| author_sort | Zhou, Jingying |
| collection | NTU |
| description | Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy. |
| first_indexed | 2024-10-01T05:13:39Z |
| format | Journal Article |
| id | ntu-10356/171559 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:13:39Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1715592023-11-05T15:39:30Z Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis Zhou, Jingying Wang, Huanyu Shu, Ting Wang, Jing Yang, Weiqin Li, Jingqing Ding, Lipeng Liu, Man Sun, Hanyong Wong, John Lai, Paul Bo-San Tsang, Shun-Wa Ward, Simon E. Chow, King-Lau Sung, Joseph Jao Yiu Cheng, Alfred Sze-Lok Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Microenvironment Molecular Biology Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy. Published version This project is supported by the University Grants Committee through General Research Fund (14108219, 14115820, 14120621), Collaborative Research Fund (C4045-18W), the Li Ka Shing Foundation, the Strategic Seed Funding for Collaborative Research Scheme (2021-22), and the Health and Medical Research Fund (03141376; 07180556). 2023-10-31T01:10:10Z 2023-10-31T01:10:10Z 2023 Journal Article Zhou, J., Wang, H., Shu, T., Wang, J., Yang, W., Li, J., Ding, L., Liu, M., Sun, H., Wong, J., Lai, P. B., Tsang, S., Ward, S. E., Chow, K., Sung, J. J. Y. & Cheng, A. S. (2023). Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis. IScience, 26(10), 107626-. https://dx.doi.org/10.1016/j.isci.2023.107626 2589-0042 https://hdl.handle.net/10356/171559 10.1016/j.isci.2023.107626 37731616 2-s2.0-85170698796 10 26 107626 en iScience © 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Science::Medicine Microenvironment Molecular Biology Zhou, Jingying Wang, Huanyu Shu, Ting Wang, Jing Yang, Weiqin Li, Jingqing Ding, Lipeng Liu, Man Sun, Hanyong Wong, John Lai, Paul Bo-San Tsang, Shun-Wa Ward, Simon E. Chow, King-Lau Sung, Joseph Jao Yiu Cheng, Alfred Sze-Lok Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title | Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title_full | Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title_fullStr | Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title_full_unstemmed | Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title_short | Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis |
| title_sort | myeloid intrinsic cell cycle related kinase drives immunosuppression to promote tumorigenesis |
| topic | Science::Medicine Microenvironment Molecular Biology |
| url | https://hdl.handle.net/10356/171559 |
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