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Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in st...

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Autores principales: Zhao, Qing, He, Xuexin, Qin, Xiyi, Liu, Yu, Jiang, Han, Wang, Jing, Wu, Shuang, Zhou, Rui, Yu, Congcong, Liu, Suling, Zhang, Hong, Tian, Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259940/
https://www.ncbi.nlm.nih.gov/pubmed/35812418
http://dx.doi.org/10.3389/fimmu.2022.938439
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author Zhao, Qing
He, Xuexin
Qin, Xiyi
Liu, Yu
Jiang, Han
Wang, Jing
Wu, Shuang
Zhou, Rui
Yu, Congcong
Liu, Suling
Zhang, Hong
Tian, Mei
author_facet Zhao, Qing
He, Xuexin
Qin, Xiyi
Liu, Yu
Jiang, Han
Wang, Jing
Wu, Shuang
Zhou, Rui
Yu, Congcong
Liu, Suling
Zhang, Hong
Tian, Mei
author_sort Zhao, Qing
collection PubMed
description Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells’ infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment.
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spelling pubmed-92599402022-07-08 Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer Zhao, Qing He, Xuexin Qin, Xiyi Liu, Yu Jiang, Han Wang, Jing Wu, Shuang Zhou, Rui Yu, Congcong Liu, Suling Zhang, Hong Tian, Mei Front Immunol Immunology Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells’ infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment. Frontiers Media S.A. 2022-06-23 /pmc/articles/PMC9259940/ /pubmed/35812418 http://dx.doi.org/10.3389/fimmu.2022.938439 Text en Copyright © 2022 Zhao, He, Qin, Liu, Jiang, Wang, Wu, Zhou, Yu, Liu, Zhang and Tian 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 Immunology
Zhao, Qing
He, Xuexin
Qin, Xiyi
Liu, Yu
Jiang, Han
Wang, Jing
Wu, Shuang
Zhou, Rui
Yu, Congcong
Liu, Suling
Zhang, Hong
Tian, Mei
Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title_full Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title_fullStr Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title_full_unstemmed Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title_short Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
title_sort enhanced therapeutic efficacy of combining losartan and chemo-immunotherapy for triple negative breast cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259940/
https://www.ncbi.nlm.nih.gov/pubmed/35812418
http://dx.doi.org/10.3389/fimmu.2022.938439
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