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IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer

Regulatory T cells (Tregs) are immunosuppressive cells involved in antitumor immunity. However, the regulation of Treg generation by inflammation in the tumor microenvironment has not been carefully investigated. Here, we demonstrated that IL-21-polarized inflammation was enriched in the tumor micro...

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Autores principales: Zhao, Yi, Zhang, Zhiyu, Lei, Wenbin, Wei, Yi, Ma, Renqiang, Wen, Yihui, Wei, Fanqin, Fan, Jun, Xu, Yang, Chen, Lin, Lyu, Kexing, Lin, Hanqing, Wen, Weiping, Sun, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131831/
https://www.ncbi.nlm.nih.gov/pubmed/34026621
http://dx.doi.org/10.3389/fonc.2021.648293
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author Zhao, Yi
Zhang, Zhiyu
Lei, Wenbin
Wei, Yi
Ma, Renqiang
Wen, Yihui
Wei, Fanqin
Fan, Jun
Xu, Yang
Chen, Lin
Lyu, Kexing
Lin, Hanqing
Wen, Weiping
Sun, Wei
author_facet Zhao, Yi
Zhang, Zhiyu
Lei, Wenbin
Wei, Yi
Ma, Renqiang
Wen, Yihui
Wei, Fanqin
Fan, Jun
Xu, Yang
Chen, Lin
Lyu, Kexing
Lin, Hanqing
Wen, Weiping
Sun, Wei
author_sort Zhao, Yi
collection PubMed
description Regulatory T cells (Tregs) are immunosuppressive cells involved in antitumor immunity. However, the regulation of Treg generation by inflammation in the tumor microenvironment has not been carefully investigated. Here, we demonstrated that IL-21-polarized inflammation was enriched in the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) and that IL-21 could promote PD-L1-induced Treg generation in a PD-1-dependent manner. Moreover, generated Tregs showed a greater ability to suppress the proliferation of tumor-associated antigen (TAA)-specific T cells than naturally occurring Tregs. Importantly, an anti-PD-1 antibody could inhibit only Treg expansion induced by clinical tumor explants with high expression of IL-21/PD-L1. In addition, neutralizing IL-21 could enhance the anti-PD-1 antibody-mediated inhibitory effect on Treg expansion. Furthermore, simultaneous high expression of IL-21 and PD-L1 was associated with more Treg infiltrates and predicted reduced overall and disease-free survival in patients with HNSCC. These findings indicate that IL-21 in the tumor microenvironment may promote PD-L1-induced, Treg-mediated immune escape in a PD-1-dependent manner and that an IL-21 neutralization strategy may enhance PD-1 blockade-based antitumor immunotherapy by targeting Treg-mediated immune evasion in patients with high expression of IL-21 and PD-L1.
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spelling pubmed-81318312021-05-20 IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer Zhao, Yi Zhang, Zhiyu Lei, Wenbin Wei, Yi Ma, Renqiang Wen, Yihui Wei, Fanqin Fan, Jun Xu, Yang Chen, Lin Lyu, Kexing Lin, Hanqing Wen, Weiping Sun, Wei Front Oncol Oncology Regulatory T cells (Tregs) are immunosuppressive cells involved in antitumor immunity. However, the regulation of Treg generation by inflammation in the tumor microenvironment has not been carefully investigated. Here, we demonstrated that IL-21-polarized inflammation was enriched in the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) and that IL-21 could promote PD-L1-induced Treg generation in a PD-1-dependent manner. Moreover, generated Tregs showed a greater ability to suppress the proliferation of tumor-associated antigen (TAA)-specific T cells than naturally occurring Tregs. Importantly, an anti-PD-1 antibody could inhibit only Treg expansion induced by clinical tumor explants with high expression of IL-21/PD-L1. In addition, neutralizing IL-21 could enhance the anti-PD-1 antibody-mediated inhibitory effect on Treg expansion. Furthermore, simultaneous high expression of IL-21 and PD-L1 was associated with more Treg infiltrates and predicted reduced overall and disease-free survival in patients with HNSCC. These findings indicate that IL-21 in the tumor microenvironment may promote PD-L1-induced, Treg-mediated immune escape in a PD-1-dependent manner and that an IL-21 neutralization strategy may enhance PD-1 blockade-based antitumor immunotherapy by targeting Treg-mediated immune evasion in patients with high expression of IL-21 and PD-L1. Frontiers Media S.A. 2021-05-05 /pmc/articles/PMC8131831/ /pubmed/34026621 http://dx.doi.org/10.3389/fonc.2021.648293 Text en Copyright © 2021 Zhao, Zhang, Lei, Wei, Ma, Wen, Wei, Fan, Xu, Chen, Lyu, Lin, Wen and Sun 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 Oncology
Zhao, Yi
Zhang, Zhiyu
Lei, Wenbin
Wei, Yi
Ma, Renqiang
Wen, Yihui
Wei, Fanqin
Fan, Jun
Xu, Yang
Chen, Lin
Lyu, Kexing
Lin, Hanqing
Wen, Weiping
Sun, Wei
IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title_full IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title_fullStr IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title_full_unstemmed IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title_short IL-21 Is an Accomplice of PD-L1 in the Induction of PD-1-Dependent Treg Generation in Head and Neck Cancer
title_sort il-21 is an accomplice of pd-l1 in the induction of pd-1-dependent treg generation in head and neck cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131831/
https://www.ncbi.nlm.nih.gov/pubmed/34026621
http://dx.doi.org/10.3389/fonc.2021.648293
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