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Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent us...

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Autores principales: Xie, Zhiqi, Kawasaki, Takahiro, Zhou, Haoyang, Okuzaki, Daisuke, Okada, Naoki, Tachibana, Masashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081766/
https://www.ncbi.nlm.nih.gov/pubmed/35548341
http://dx.doi.org/10.3389/fphar.2022.873792
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author Xie, Zhiqi
Kawasaki, Takahiro
Zhou, Haoyang
Okuzaki, Daisuke
Okada, Naoki
Tachibana, Masashi
author_facet Xie, Zhiqi
Kawasaki, Takahiro
Zhou, Haoyang
Okuzaki, Daisuke
Okada, Naoki
Tachibana, Masashi
author_sort Xie, Zhiqi
collection PubMed
description Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent used for the treatment of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. However, several reports have revealed that G-CSF plays crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited enhanced proliferation and immunosuppressive activity compared to those differentiated without G-CSF. RNA sequencing analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs by upregulating gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, administration of recombinant G-CSF increased the number of MDSCs and attenuated the anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, could prevent G-CSF-induced tumor growth, without affecting the promotion of myelopoiesis by G-CSF. These results suggest that targeting GGT1 can mitigate G-CSF-induced enhanced immunosuppressive functions of MDSCs and can eliminate the tumor-promoting effect of G-CSF. Furthermore, GGsTop could be an attractive combination agent during G-CSF treatment for FN in patients with cancer.
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spelling pubmed-90817662022-05-10 Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF Xie, Zhiqi Kawasaki, Takahiro Zhou, Haoyang Okuzaki, Daisuke Okada, Naoki Tachibana, Masashi Front Pharmacol Pharmacology Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent used for the treatment of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. However, several reports have revealed that G-CSF plays crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited enhanced proliferation and immunosuppressive activity compared to those differentiated without G-CSF. RNA sequencing analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs by upregulating gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, administration of recombinant G-CSF increased the number of MDSCs and attenuated the anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, could prevent G-CSF-induced tumor growth, without affecting the promotion of myelopoiesis by G-CSF. These results suggest that targeting GGT1 can mitigate G-CSF-induced enhanced immunosuppressive functions of MDSCs and can eliminate the tumor-promoting effect of G-CSF. Furthermore, GGsTop could be an attractive combination agent during G-CSF treatment for FN in patients with cancer. Frontiers Media S.A. 2022-04-25 /pmc/articles/PMC9081766/ /pubmed/35548341 http://dx.doi.org/10.3389/fphar.2022.873792 Text en Copyright © 2022 Xie, Kawasaki, Zhou, Okuzaki, Okada and Tachibana. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Xie, Zhiqi
Kawasaki, Takahiro
Zhou, Haoyang
Okuzaki, Daisuke
Okada, Naoki
Tachibana, Masashi
Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title_full Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title_fullStr Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title_full_unstemmed Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title_short Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF
title_sort targeting ggt1 eliminates the tumor-promoting effect and enhanced immunosuppressive function of myeloid-derived suppressor cells caused by g-csf
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081766/
https://www.ncbi.nlm.nih.gov/pubmed/35548341
http://dx.doi.org/10.3389/fphar.2022.873792
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