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Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment
BACKGROUND: Patients with triple-negative breast cancer (TNBC) are better responders to neoadjuvant chemotherapy; however, they are poor in the durability of response with decreased overall and progression-free survival. METHODS: Given that significant improvements have been reported with PD-L1-PD-1...
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/PMC9206753/ https://www.ncbi.nlm.nih.gov/pubmed/35717238 http://dx.doi.org/10.1186/s12967-022-03474-9 |
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author | Yang, Zhao-ying Jiang, Cheng-wei Zhang, Wen-long Sun, Guang |
author_facet | Yang, Zhao-ying Jiang, Cheng-wei Zhang, Wen-long Sun, Guang |
author_sort | Yang, Zhao-ying |
collection | PubMed |
description | BACKGROUND: Patients with triple-negative breast cancer (TNBC) are better responders to neoadjuvant chemotherapy; however, they are poor in the durability of response with decreased overall and progression-free survival. METHODS: Given that significant improvements have been reported with PD-L1-PD-1 blockade in different cancers, we evaluated the in vitro and in vivo effectiveness of Tomivosertib (eFT-508), an anthracycline, adriamycin, and MNK1/2 inhibitor, which has been previously shown to inhibit translation of PD-L1 in mice model of liver cancer, alone or in combination using BC cell lines and an orthotopic xenograft mice model using the TNBC cell line MDA-MB-231. RESULTS: Within the context of The Cancer Genome Atlas (TCGA) dataset, expression of CD274 mRNA, which encodes programmed death-ligand 1 (PD-L1), was found to be significantly overexpressed in TNBC patients compared to patients with HER2 + or luminal breast cancer (BC). Even within TNBC sub-types, CD274 expression was significantly higher in the immune modulatory subtype (TNBC-IM). BC cells exhibited high IC(50) = 0.85 ± 0.07 nM with Adriamycin and significantly lower IC(50) = 0.23 ± 0.04 nM with eFT-508 (P < 0.01). Combination treatment showed in vitro synergism on chemosensitivity. Combination therapy also exhibited a synergistic effect on inhibition of tumor growth and lung colonization in vivo. Mass cytometry-based evaluation of the tumor microenvironment revealed significant attenuation of both PD-L1 and PD-L2 following mono- or combination therapy with eFT-508. CONCLUSIONS: Treatment with eFT-508 restored effector and cytotoxic function of tumor-infiltrating CD8 + T cells in mice. The remarkable efficacy observed both in vitro and in vivo, and clinical synergism with adriamycin, highlights the potential of eFT-508 as an alternative, yet more efficacious, therapeutic option for patients with TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03474-9. |
format | Online Article Text |
id | pubmed-9206753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-92067532022-06-20 Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment Yang, Zhao-ying Jiang, Cheng-wei Zhang, Wen-long Sun, Guang J Transl Med Research BACKGROUND: Patients with triple-negative breast cancer (TNBC) are better responders to neoadjuvant chemotherapy; however, they are poor in the durability of response with decreased overall and progression-free survival. METHODS: Given that significant improvements have been reported with PD-L1-PD-1 blockade in different cancers, we evaluated the in vitro and in vivo effectiveness of Tomivosertib (eFT-508), an anthracycline, adriamycin, and MNK1/2 inhibitor, which has been previously shown to inhibit translation of PD-L1 in mice model of liver cancer, alone or in combination using BC cell lines and an orthotopic xenograft mice model using the TNBC cell line MDA-MB-231. RESULTS: Within the context of The Cancer Genome Atlas (TCGA) dataset, expression of CD274 mRNA, which encodes programmed death-ligand 1 (PD-L1), was found to be significantly overexpressed in TNBC patients compared to patients with HER2 + or luminal breast cancer (BC). Even within TNBC sub-types, CD274 expression was significantly higher in the immune modulatory subtype (TNBC-IM). BC cells exhibited high IC(50) = 0.85 ± 0.07 nM with Adriamycin and significantly lower IC(50) = 0.23 ± 0.04 nM with eFT-508 (P < 0.01). Combination treatment showed in vitro synergism on chemosensitivity. Combination therapy also exhibited a synergistic effect on inhibition of tumor growth and lung colonization in vivo. Mass cytometry-based evaluation of the tumor microenvironment revealed significant attenuation of both PD-L1 and PD-L2 following mono- or combination therapy with eFT-508. CONCLUSIONS: Treatment with eFT-508 restored effector and cytotoxic function of tumor-infiltrating CD8 + T cells in mice. The remarkable efficacy observed both in vitro and in vivo, and clinical synergism with adriamycin, highlights the potential of eFT-508 as an alternative, yet more efficacious, therapeutic option for patients with TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03474-9. BioMed Central 2022-06-18 /pmc/articles/PMC9206753/ /pubmed/35717238 http://dx.doi.org/10.1186/s12967-022-03474-9 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 Yang, Zhao-ying Jiang, Cheng-wei Zhang, Wen-long Sun, Guang Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title | Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title_full | Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title_fullStr | Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title_full_unstemmed | Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title_short | Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
title_sort | treatment with eft-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206753/ https://www.ncbi.nlm.nih.gov/pubmed/35717238 http://dx.doi.org/10.1186/s12967-022-03474-9 |
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