Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model

• Published in: International journal of molecular sciences Vol. 21; no. 1; p. 170
• Main Authors: Balog, József Á, Hackler, Jr, László, Kovács, Anita K, Neuperger, Patrícia, Alföldi, Róbert, Nagy, Lajos I, Puskás, László G, Szebeni, Gábor J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25-12-2019; MDPI
• Subjects: Animals; Bone marrow; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; CD11b antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; CD44 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cytometry; Cytotoxicity; Dosage; Down-Regulation - drug effects; Enzymes; Female; Fibroblasts; Gelatinases - metabolism; Humans; Hyaluronan Receptors - metabolism; Immunomodulation; Immunophenotyping; Immunotherapy; Interferon-gamma - metabolism; Interleukin-17 - metabolism; L-selectin; Lungs; Lymphatic system; Lymphocytes B; Lymphocytes T; Membrane Proteins - metabolism; Metastases; Metastasis; metastatic breast cancer; Mice; Mice, Inbred BALB C; Myeloid cells; myeloid-derived suppressor cells; Myeloid-Derived Suppressor Cells - cytology; Myeloid-Derived Suppressor Cells - metabolism; Neoplastic Cells, Circulating - metabolism; Peptides; Proteolysis; Serine Endopeptidases - metabolism; single cell mass cytometry; Spleen; Splenomegaly; Stroma; Suppressor cells; Transplantation, Heterologous; Tumors; γ-Interferon; single cell mass cytometry; immunophenotyping; myeloid-derived suppressor cells; metastatic breast cancer
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010170

The treatment of metastatic breast cancer remained a challenge despite the recent breakthrough in the immunotherapy regimens. Here, we addressed the multidimensional immunophenotyping of 4T1 metastatic breast cancer by the state-of-the-art single cell mass cytometry (CyTOF). We determined the dose and time dependent cytotoxicity of cisplatin on 4T1 cells by the xCelligence real-time electronic sensing assay. Cisplatin treatment reduced tumor growth, number of lung metastasis, and the splenomegaly of 4T1 tumor bearing mice. We showed that cisplatin inhibited the tumor stroma formation, the polarization of carcinoma-associated fibroblasts by the diminished proteolytic activity of fibroblast activating protein. The CyTOF analysis revealed the emergence of CD11b+/Gr-1+/CD44+ or CD11b+/Gr-1+/IL-17A+ myeloid-derived suppressor cells (MDSCs) and the absence of B220+ or CD62L+ B-cells, the CD62L+/CD4+ and CD62L+/CD8+ T-cells in the spleen of advanced cancer. We could show the immunomodulatory effect of cisplatin via the suppression of splenic MDSCs and via the promotion of peripheral IFN-γ+ myeloid cells. Our data could support the use of low dose chemotherapy with cisplatin as an immunomodulatory agent for metastatic triple negative breast cancer.