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Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity

Although current cancer immunotherapies that target PD-1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor...

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Autores principales: Zheng, Shuang, Song, Jiaming, Linghu, Dongli, Yang, Riyao, Liu, Boning, Xue, Zhen, Chen, Qihui, Liu, Chengjie, Zhong, Diansheng, Hung, Mien-Chie, Sun, Linlin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909994/
https://www.ncbi.nlm.nih.gov/pubmed/36778120
http://dx.doi.org/10.7150/ijbs.79852
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author Zheng, Shuang
Song, Jiaming
Linghu, Dongli
Yang, Riyao
Liu, Boning
Xue, Zhen
Chen, Qihui
Liu, Chengjie
Zhong, Diansheng
Hung, Mien-Chie
Sun, Linlin
author_facet Zheng, Shuang
Song, Jiaming
Linghu, Dongli
Yang, Riyao
Liu, Boning
Xue, Zhen
Chen, Qihui
Liu, Chengjie
Zhong, Diansheng
Hung, Mien-Chie
Sun, Linlin
author_sort Zheng, Shuang
collection PubMed
description Although current cancer immunotherapies that target PD-1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor potential of T cells and benefit more patients. Galectin-9 (Gal-9), initially identified as a ligand for TIM-3 to induce T cell death, acts as an immunosuppressive regulator in the tumor microenvironment (TME) but its potential as a therapeutic target remains largely elusive. Here we show that antibody neutralization of Gal-9, in combination with inhibition of Ataxia telangiectasia mutated (ATM), a kinase essential for DNA damage response (DDR), is a promising modality for cancer immunotherapy. Genetic depletion of ATM in tumors markedly potentiated anti-Gal-9 therapy in a syngeneic mouse model. Mechanistically, ATM inhibition greatly upregulated Gal-9 expression and secretion in a variety of human and murine tumor cells via the cGAS-STING-interferon β (IFNβ) innate immune pathway. Combination of Gal-9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFNβ signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade.
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spelling pubmed-99099942023-02-09 Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity Zheng, Shuang Song, Jiaming Linghu, Dongli Yang, Riyao Liu, Boning Xue, Zhen Chen, Qihui Liu, Chengjie Zhong, Diansheng Hung, Mien-Chie Sun, Linlin Int J Biol Sci Research Paper Although current cancer immunotherapies that target PD-1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor potential of T cells and benefit more patients. Galectin-9 (Gal-9), initially identified as a ligand for TIM-3 to induce T cell death, acts as an immunosuppressive regulator in the tumor microenvironment (TME) but its potential as a therapeutic target remains largely elusive. Here we show that antibody neutralization of Gal-9, in combination with inhibition of Ataxia telangiectasia mutated (ATM), a kinase essential for DNA damage response (DDR), is a promising modality for cancer immunotherapy. Genetic depletion of ATM in tumors markedly potentiated anti-Gal-9 therapy in a syngeneic mouse model. Mechanistically, ATM inhibition greatly upregulated Gal-9 expression and secretion in a variety of human and murine tumor cells via the cGAS-STING-interferon β (IFNβ) innate immune pathway. Combination of Gal-9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFNβ signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade. Ivyspring International Publisher 2023-01-16 /pmc/articles/PMC9909994/ /pubmed/36778120 http://dx.doi.org/10.7150/ijbs.79852 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zheng, Shuang
Song, Jiaming
Linghu, Dongli
Yang, Riyao
Liu, Boning
Xue, Zhen
Chen, Qihui
Liu, Chengjie
Zhong, Diansheng
Hung, Mien-Chie
Sun, Linlin
Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title_full Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title_fullStr Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title_full_unstemmed Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title_short Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity
title_sort galectin-9 blockade synergizes with atm inhibition to induce potent anti-tumor immunity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909994/
https://www.ncbi.nlm.nih.gov/pubmed/36778120
http://dx.doi.org/10.7150/ijbs.79852
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