High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets
Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory rece...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2025
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| Online Access: | https://hdl.handle.net/10356/182492 |
| _version_ | 1826116859438563328 |
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| author | Wong, Brandon Han Siang Poh, Zhi Sheng Tan, James Chia Wei Amuthavalli, Kottaiswamy Ho, Ying Swan Chen, Shuwen Mak, Shi Ya Bi, Xuezhi Webster, Richard David Shelat, Vishalkumar G. Chandy, Kanianthara George Verma, Navin Kumar |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Wong, Brandon Han Siang Poh, Zhi Sheng Tan, James Chia Wei Amuthavalli, Kottaiswamy Ho, Ying Swan Chen, Shuwen Mak, Shi Ya Bi, Xuezhi Webster, Richard David Shelat, Vishalkumar G. Chandy, Kanianthara George Verma, Navin Kumar |
| author_sort | Wong, Brandon Han Siang |
| collection | NTU |
| description | Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME. |
| first_indexed | 2025-03-09T11:45:47Z |
| format | Journal Article |
| id | ntu-10356/182492 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-03-09T11:45:47Z |
| publishDate | 2025 |
| record_format | dspace |
| spelling | ntu-10356/1824922025-02-09T15:40:27Z High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets Wong, Brandon Han Siang Poh, Zhi Sheng Tan, James Chia Wei Amuthavalli, Kottaiswamy Ho, Ying Swan Chen, Shuwen Mak, Shi Ya Bi, Xuezhi Webster, Richard David Shelat, Vishalkumar G. Chandy, Kanianthara George Verma, Navin Kumar Lee Kong Chian School of Medicine (LKCMedicine) School of Chemistry, Chemical Engineering and Biotechnology Tan Tock Seng Hospital National Skin Centre, Singapore Skin Research Institute of Singapore NTU Institute for Health Technologies Medicine, Health and Life Sciences Immune suppression Metabolomics Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME. Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This research was supported, in part, by the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 2 Grant (MOE2017-T2-2-004), AcRF Tier 1 Grant (2020-T1-001-062) and the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). Navin Kumar Verma was a recipient of these grants. Brandon Han Siang Wong and Zhi Sheng Poh are recipients of PhD fellowships from HealthTech NTU and Lee Kong Chian School of Medicine, Nanyang Technological University Singapore. 2025-02-04T08:22:05Z 2025-02-04T08:22:05Z 2024 Journal Article Wong, B. H. S., Poh, Z. S., Tan, J. C. W., Amuthavalli, K., Ho, Y. S., Chen, S., Mak, S. Y., Bi, X., Webster, R. D., Shelat, V. G., Chandy, K. G. & Verma, N. K. (2024). High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets. European Journal of Immunology, e202451440-. https://dx.doi.org/10.1002/eji.202451440 0014-2980 https://hdl.handle.net/10356/182492 10.1002/eji.202451440 39651799 2-s2.0-85211249674 e202451440 en MOE2017-T2-2-004 2020-T1-001-062 OFLCG18May-0028 European Journal of Immunology © 2024 The Author(s). European Journal of Immunology published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the originalwork is properly cited and is not used for commercial purposes. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Immune suppression Metabolomics Wong, Brandon Han Siang Poh, Zhi Sheng Tan, James Chia Wei Amuthavalli, Kottaiswamy Ho, Ying Swan Chen, Shuwen Mak, Shi Ya Bi, Xuezhi Webster, Richard David Shelat, Vishalkumar G. Chandy, Kanianthara George Verma, Navin Kumar High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title | High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title_full | High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title_fullStr | High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title_full_unstemmed | High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title_short | High extracellular K+ skews T-cell differentiation towards tumour promoting Th2 and Treg subsets |
| title_sort | high extracellular k skews t cell differentiation towards tumour promoting th2 and treg subsets |
| topic | Medicine, Health and Life Sciences Immune suppression Metabolomics |
| url | https://hdl.handle.net/10356/182492 |
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