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Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer

OBJECTIVE: TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. METHODS: The expression of CD155 and TIGIT in cervical cancer ti...

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Autores principales: Liu, Lu, Wang, Aihong, Liu, Xiaoli, Han, Sai, Sun, Yu, Zhang, Junhua, Guo, Lingyu, Zhang, Youzhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210727/
https://www.ncbi.nlm.nih.gov/pubmed/35729552
http://dx.doi.org/10.1186/s12967-022-03480-x
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author Liu, Lu
Wang, Aihong
Liu, Xiaoli
Han, Sai
Sun, Yu
Zhang, Junhua
Guo, Lingyu
Zhang, Youzhong
author_facet Liu, Lu
Wang, Aihong
Liu, Xiaoli
Han, Sai
Sun, Yu
Zhang, Junhua
Guo, Lingyu
Zhang, Youzhong
author_sort Liu, Lu
collection PubMed
description OBJECTIVE: TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. METHODS: The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8(+) T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling. RESULTS: TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8(+) T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8(+) T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8(+) T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8(+) T cells attenuates the inhibitory effect of SHIP-1 on CD8(+) T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8(+) T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8(+) T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody. CONCLUSIONS: Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03480-x.
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spelling pubmed-92107272022-06-22 Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer Liu, Lu Wang, Aihong Liu, Xiaoli Han, Sai Sun, Yu Zhang, Junhua Guo, Lingyu Zhang, Youzhong J Transl Med Research OBJECTIVE: TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. METHODS: The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8(+) T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling. RESULTS: TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8(+) T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8(+) T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8(+) T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8(+) T cells attenuates the inhibitory effect of SHIP-1 on CD8(+) T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8(+) T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8(+) T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody. CONCLUSIONS: Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03480-x. BioMed Central 2022-06-21 /pmc/articles/PMC9210727/ /pubmed/35729552 http://dx.doi.org/10.1186/s12967-022-03480-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Liu, Lu
Wang, Aihong
Liu, Xiaoli
Han, Sai
Sun, Yu
Zhang, Junhua
Guo, Lingyu
Zhang, Youzhong
Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title_full Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title_fullStr Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title_full_unstemmed Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title_short Blocking TIGIT/CD155 signalling reverses CD8(+) T cell exhaustion and enhances the antitumor activity in cervical cancer
title_sort blocking tigit/cd155 signalling reverses cd8(+) t cell exhaustion and enhances the antitumor activity in cervical cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210727/
https://www.ncbi.nlm.nih.gov/pubmed/35729552
http://dx.doi.org/10.1186/s12967-022-03480-x
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