Epithelial-to-mesenchymal Transition Heterogeneity of Circulating Tumor Cells and Their Correlation With MDSCs and Tregs in HER2-negative Metastatic Breast Cancer Patients
- 30 January 2021
- journal article
- research article
- Published by Anticancer Research USA Inc. in Anticancer Research
- Vol. 41 (2), 661-670
- https://doi.org/10.21873/anticanres.14817
Abstract
Background: To investigate the correlation between circulating tumor cells (CTCs) bearing cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) phenotypes and the different immunosuppressive cells in peripheral blood of patients with metastatic breast cancer (mBC). Materials and Methods: Blood was obtained from 38 pre-treated patients with mBC before a new line of treatment. CTC detection and characterization was performed by triple immunofluorescent staining, while Myeloid-derived Suppressor Cells (MDSCs) and T regulatory cells (Tregs) were analyzed by multi-flow cytometry. Results: CTCs were detected in 16 (42.1%) of patients. Based on the co-expression of ALDH1, TWIST and CK, CTCs revealed an important heterogeneity: CTCs with a CSC/partial-EMT, CSC/Epithelial-like, non-CSC/partial-EMT and non-CSC/Epithelial-like phenotype were detected in 7 (18.4%), 7 (18.4%), 1 (1.4%) and 9 (23.7%) of patients, respectively. Immunophenotyping of MDSCs identified 2 monocytic [M-MDSCs; CD14+CD15+CD11b+CD33+HLA-DR−Lin− (CD14+CD15+) and CD14+CD15–CD11b+CD33+ HLA-DR−Lin− (CD14+CD15–)] and one granulocytic [G-MDSCs; CD14−CD15+CD11b+CD33+HLA-DR−Lin− (CD14– CD15+)] subpopulations, expressing inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS), respectively. Patients with detectable CTCs had a higher frequency of Tregs (CD3+CD4+CD25high; p=0.022) whereas a positive correlation was found between CTC counts and the percentage of Tregs (p=0.005) and CD14+CD15+ M-MDSCs (p=0.024). Patients with a partial-EMT phenotype had a higher frequency of CD14+CD15+ M-MDSCs (p=0.023). Patients harboring the non-CSC/epithelial-like CTC subpopulation had an increased frequency of CD14-CD15+ G-MDSCs (p=0.020), along with decreased levels of CD3+CD4+CD25high FoxP3+ Tregs (p=0.020). Conclusion: These findings provide evidence that CTCs in ER+/HER2– mBC patients may be under the control of the immune system and various immune escape mechanisms might be involved during the different stages of their biological evolution.Keywords
This publication has 53 references indexed in Scilit:
- Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patientsCellular Immunology, 2011
- Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13Cancer Immunology, Immunotherapy, 2011
- Immune Promotion of Epithelial-mesenchymal Transition and Generation of Breast Cancer Stem CellsCancer Research, 2010
- Modulation of T-Cell Activation by Malignant Melanoma Initiating CellsCancer Research, 2010
- Identification and targeting of cancer stem cellsBioEssays, 2009
- Immune-Induced Epithelial to Mesenchymal Transition In vivo Generates Breast Cancer Stem CellsCancer Research, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapyCancer Immunology, Immunotherapy, 2008
- Regulatory T cells and treatment of cancerCurrent Opinion in Immunology, 2008
- Identification of cells initiating human melanomasNature, 2008