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Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy
BACKGROUND: Myeloid‐derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9756281/ https://www.ncbi.nlm.nih.gov/pubmed/36521929 http://dx.doi.org/10.1136/jitc-2022-005769 |
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author | Peng, Peng Lou, Yue Wang, Shicheng Wang, Junjun Zhang, Zelu Du, Peishan Zheng, Jiamin Liu, Ping Xu, Lisa X |
author_facet | Peng, Peng Lou, Yue Wang, Shicheng Wang, Junjun Zhang, Zelu Du, Peishan Zheng, Jiamin Liu, Ping Xu, Lisa X |
author_sort | Peng, Peng |
collection | PubMed |
description | BACKGROUND: Myeloid‐derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4(+) Th1-dominant immune response, but the mechanism regulating this process remains unclear. METHODS: NK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors. RESULTS: NK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4(+) Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes. CONCLUSIONS: Cryo-thermal therapy induces effective CD4(+) Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy. |
format | Online Article Text |
id | pubmed-9756281 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-97562812022-12-17 Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy Peng, Peng Lou, Yue Wang, Shicheng Wang, Junjun Zhang, Zelu Du, Peishan Zheng, Jiamin Liu, Ping Xu, Lisa X J Immunother Cancer Basic Tumor Immunology BACKGROUND: Myeloid‐derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4(+) Th1-dominant immune response, but the mechanism regulating this process remains unclear. METHODS: NK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors. RESULTS: NK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4(+) Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes. CONCLUSIONS: Cryo-thermal therapy induces effective CD4(+) Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy. BMJ Publishing Group 2022-12-15 /pmc/articles/PMC9756281/ /pubmed/36521929 http://dx.doi.org/10.1136/jitc-2022-005769 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Peng, Peng Lou, Yue Wang, Shicheng Wang, Junjun Zhang, Zelu Du, Peishan Zheng, Jiamin Liu, Ping Xu, Lisa X Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title | Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title_full | Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title_fullStr | Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title_full_unstemmed | Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title_short | Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy |
title_sort | activated nk cells reprogram mdscs via nkg2d-nkg2dl and ifn-γ to modulate antitumor t-cell response after cryo-thermal therapy |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9756281/ https://www.ncbi.nlm.nih.gov/pubmed/36521929 http://dx.doi.org/10.1136/jitc-2022-005769 |
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