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

Yiran Si,¹ Jian Yue,² Zhaoyang Liu,³ Mo Li,³ Feng Du,⁴ Xue Wang,² Zhong Dai,⁵ Nanlin Hu,¹ Jie Ju,¹ Songlin Gao,¹ Xiaobing Wang,³ Peng Yuan<sup>2

1</sup>Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; ²Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; ³State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; ⁴China Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; ⁵Department of Medical Oncology, Cancer Hospital of Huanxing Chaoyang District, Beijing, 100005, People’s Republic of China

Correspondence: Peng Yuan
Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Pan Jia Yuan Nan Li, Chao Yang District, Beijing, 100021, People’s Republic of China
Tel +86 10-87787245
Email [email protected]
Xiaobing Wang
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Pan Jia Yuan Nan Li, Chao Yang District, Beijing, 100021, People’s Republic of China
Tel +86 10-87788430
Email [email protected]

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: breast cancer, immune response, phase-transformation nanoparticles, immunogenic cell death, DC maturation