Frontiers in Immunology (Jun 2022)
Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer
- Qing Zhao,
- Qing Zhao,
- Qing Zhao,
- Xuexin He,
- Xiyi Qin,
- Xiyi Qin,
- Xiyi Qin,
- Yu Liu,
- Yu Liu,
- Yu Liu,
- Han Jiang,
- Jing Wang,
- Jing Wang,
- Jing Wang,
- Shuang Wu,
- Shuang Wu,
- Shuang Wu,
- Rui Zhou,
- Rui Zhou,
- Rui Zhou,
- Congcong Yu,
- Congcong Yu,
- Congcong Yu,
- Suling Liu,
- Hong Zhang,
- Hong Zhang,
- Hong Zhang,
- Hong Zhang,
- Hong Zhang,
- Mei Tian,
- Mei Tian,
- Mei Tian,
- Mei Tian
Affiliations
- Qing Zhao
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Qing Zhao
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Qing Zhao
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Xuexin He
- Department of Medical Oncology, Huashan Hospital of Fudan University, Shanghai, China
- Xiyi Qin
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Xiyi Qin
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Xiyi Qin
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Yu Liu
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Yu Liu
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Yu Liu
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Han Jiang
- Positron Emission Tomography-Computed Tomography (PET-CT) Center, Fujian Medical University Union Hospital, Fuzhou, China
- Jing Wang
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Jing Wang
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Jing Wang
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Shuang Wu
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Shuang Wu
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Shuang Wu
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Rui Zhou
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Rui Zhou
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Rui Zhou
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Congcong Yu
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Congcong Yu
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Congcong Yu
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Fudan University, Shanghai, China
- Hong Zhang
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Hong Zhang
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Hong Zhang
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Hong Zhang
- College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China
- Hong Zhang
- Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China
- Mei Tian
- Department of Nuclear Medicine and Positron Emission Tomography (PET) Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Mei Tian
- Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou, China
- Mei Tian
- Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou, China
- Mei Tian
- Human Phenome Institute, Fudan University, Shanghai, China
- DOI
- https://doi.org/10.3389/fimmu.2022.938439
- Journal volume & issue
-
Vol. 13
Abstract
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.
Keywords
- triple-negative breast cancer
- immunotherapy
- extracellular matrix
- chemotherapy
- positron emission tomography (PET)
