Phase-Transformation Nanoparticle-Mediated Sonodynamic Therapy: An Effective Modality to Enhance Anti-Tumor Immune Response by Inducing Immunogenic Cell Death in Breast Cancer

Int J Nanomedicine. 2021 Mar 5:16:1913-1926. doi: 10.2147/IJN.S297933. eCollection 2021.

Abstract

Purpose: Immunologically quiescent of breast cancer cells has been recognized as the key impediment for the breast cancer immunotherapy. In this study, we aimed to investigate the role of nanoparticle-mediated sonodynamic therapy (SDT) in promoting anti-tumor immune of breast cancer cells and its potential immune mechanisms.

Materials and methods: The phase-transformation nanoparticles (LIP-PFH nanoparticles) were in-house prepared and its physiochemical characters were detected. The CCK-8 assay, apoptosis analysis and Balb/c tumor model establishment were used to explore the anti-tumor effect of LIP-PFH nanoparticles triggered by low-intensity focused ultrasound (LIFU) both in vitro and in vivo. Flow cytometry and immunohistochemistry of CD4+T, CD8+T, CD8+PD-1+T in blood, spleen and tumor tissue were performed to represent the change of immune response. Detection of immunogenic cell death (ICD) markers was examined to study the potential mechanisms.

Results: LIP-PFH nanoparticles triggered by LIFU could inhibit the proliferation and promote the apoptosis of 4T1 cells both in vitro and in vivo. CD4+T and CD8+T cell subsets were significantly increased in blood, spleen and tumor tissue, meanwhile CD8+PD-1+T cells were reduced, indicating enhancement of anti-tumor immune response of breast cancer cells in the nanoparticle-mediated SDT group. Detection of ICD markers (ATP, high-mobility group box B1, and calreticulin) and flow cytometric analysis of dendritic cell (DC) maturity further showed that the nanoparticle-mediated SDT can promote DC maturation to increase the proportion of cytotoxic T cells by inducing ICD of breast cancer cells.

Conclusion: The therapy of nanoparticles-mediated SDT can effectively enhance anti-tumor immune response of breast cancer.

Keywords: DC maturation; breast cancer; immune response; immunogenic cell death; phase-transformation nanoparticles.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Dendritic Cells / metabolism
  • Endocytosis
  • Female
  • Fluorocarbons / chemistry
  • Immunity*
  • Immunogenic Cell Death*
  • Immunotherapy
  • Mammary Neoplasms, Animal / immunology*
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • Ultrasonic Therapy*

Substances

  • Fluorocarbons

Grants and funding

This work was supported by the National Key R&D Program of China (2018YFC0115204), National Natural Science Foundation of China (81672634), CSCO Pilot Oncology Research Fund (Y-2019AZMS-0377), Capital Health Development Research Project (2018-2-4023), and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences Clinical and Translational Medicine Research (12019XK320071).