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Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer
BACKGROUND: Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulati...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783715/ https://www.ncbi.nlm.nih.gov/pubmed/36564797 http://dx.doi.org/10.1186/s12967-022-03807-8 |
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author | Chen, Yuru Sun, Jiazheng Luo, Yachan Liu, Jiazhou Wang, Xiaoyu Feng, Rui Huang, Jing Du, Huimin Li, Qin Tan, Jinxiang Ren, Guosheng Wang, Xiaoyi Li, Hongzhong |
author_facet | Chen, Yuru Sun, Jiazheng Luo, Yachan Liu, Jiazhou Wang, Xiaoyu Feng, Rui Huang, Jing Du, Huimin Li, Qin Tan, Jinxiang Ren, Guosheng Wang, Xiaoyi Li, Hongzhong |
author_sort | Chen, Yuru |
collection | PubMed |
description | BACKGROUND: Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic. METHODS: Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival. RESULTS: Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8(+) T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4(+) T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects. CONCLUSIONS: Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03807-8. |
format | Online Article Text |
id | pubmed-9783715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97837152022-12-24 Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer Chen, Yuru Sun, Jiazheng Luo, Yachan Liu, Jiazhou Wang, Xiaoyu Feng, Rui Huang, Jing Du, Huimin Li, Qin Tan, Jinxiang Ren, Guosheng Wang, Xiaoyi Li, Hongzhong J Transl Med Research BACKGROUND: Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic. METHODS: Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival. RESULTS: Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8(+) T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4(+) T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects. CONCLUSIONS: Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03807-8. BioMed Central 2022-12-23 /pmc/articles/PMC9783715/ /pubmed/36564797 http://dx.doi.org/10.1186/s12967-022-03807-8 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 Chen, Yuru Sun, Jiazheng Luo, Yachan Liu, Jiazhou Wang, Xiaoyu Feng, Rui Huang, Jing Du, Huimin Li, Qin Tan, Jinxiang Ren, Guosheng Wang, Xiaoyi Li, Hongzhong Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title | Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title_full | Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title_fullStr | Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title_full_unstemmed | Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title_short | Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer |
title_sort | pharmaceutical targeting th2-mediated immunity enhances immunotherapy response in breast cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783715/ https://www.ncbi.nlm.nih.gov/pubmed/36564797 http://dx.doi.org/10.1186/s12967-022-03807-8 |
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