Epithelial-to-Mesenchymal Transition Contributes to Immunosuppression in Breast Carcinomas
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Abstract
The epithelial-to-mesenchymal transition (EMT) is a cell biological program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. It is unclear, however, whether the activation of EMT in carcinoma cells can change their susceptibility to immune attack. We demonstrate here that mammary tumor cells arising from more epithelial carcinoma cell lines expressed high levels of MHC-I, low levels of PD-L1, and contained within their stroma CD8+ T cells and M1 (antitumor) macrophages. In contrast, tumors arising from more mesenchymal carcinoma cell lines exhibiting EMT markers expressed low levels of MHC-I, high levels of PD-L1, and contained within their stroma regulatory T cells, M2 (protumor) macrophages, and exhausted CD8+ T cells. Moreover, the more mesenchymal carcinoma cells within a tumor retained the ability to protect their more epithelial counterparts from immune attack. Finally, epithelial tumors were more susceptible to elimination by immunotherapy than corresponding mesenchymal tumors. Our results identify immune cells and immunomodulatory markers that can be potentially targeted to enhance the susceptibility of immunosuppressive tumors to various therapeutic regimens. Cancer Res; 77(15); 3982–9. ©2017 AACR.
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EMT enables carcinoma cells to exert local immunosuppression by repressing MHCI antigen presentation and antigen processing/presentation machinery, thereby suppressing CD8+ T cell and NK cytotoxic activities.
“Of further therapeutic relevance, EMT enables carcinoma cells to exert local immunosuppression143,144. EMT confers repression of major histocompatibility complex class I (MHCI) antigen presentation by tumor cells, which is required for recognition by CD8+ T cells, and thus indirectly suppresses cytotoxic activities of CD8+ T cells and cytolytic activities of NK cells141,143–145.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [141]
EMT confers increased cancer cell expression of PD-L1, the ligand for PD-1 on CD8+ T cells.
“EMT also confers increased cancer cell expression of PD-L1, the ligand for the immune-inhibitory PD-1 receptor on CD8+ T lymphocytes141,146.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [141]
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References 18 · Cited by 395
- Authors
- Dongre, A., Rashidian, M., Reinhardt, F., Bagnato, A., Keckesova, Z., Ploegh, H. L., & Weinberg, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Weinberg, Robert A.
- Venue
- Cancer Research
- Published
- 2017-08-01
- Volume
- 77
- Issue
- 15
- Pages
- 3982-3989
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5541771
- OpenAlex
- W2605607341
- Cited by
- 395
- References
- 18
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 39 · 2023: 58 · 2022: 52 · 2021: 53 · 2020: 52 · 2019: 37 · 2018: 31 · 2017: 8
- FWCI
- 15.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Massachusetts Institute of Technology
- National Cancer Institute (P01CA080111)
- National Institute of General Medical Sciences (DP1GM106409, R01GM100518)
- National Institute of Allergy and Infectious Diseases (R01AI087879)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- epithelial-mesenchymal transition, breast cancer, tumor immunosuppression, PD-L1, MHC class I, tumor stroma, regulatory T cells, M2 macrophages, M1 macrophages, CD8+ T cell exhaustion, tumor heterogeneity
- MeSH terms
- Animals, Breast Neoplasms, Disease Models, Animal, Female, Flow Cytometry, Fluorescent Antibody Technique, Mice, Inbred C57BL, Blotting, Western, Tumor Escape, Mice, Epithelial-Mesenchymal Transition
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