Doxorubicin Eliminates Myeloid-Derived Suppressor Cells and Enhances the Efficacy of Adoptive T-Cell Transfer in Breast Cancer
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Abstract
Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood, and tumor beds. Furthermore, residual MDSC from doxorubicin-treated mice exhibited impaired suppressive function. Importantly, the frequency of CD4+ and CD8+ T lymphocytes and consequently the effector lymphocytes or natural killer (NK) to suppressive MDSC ratios were significantly increased following doxorubicin treatment of tumor-bearing mice. In addition, the proportion of NK and cytotoxic T cell (CTL) expressing perforin and granzyme B and of CTL producing IFN-γ was augmented by doxorubicin administration. Of therapeutic relevance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. These results thus indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T-cell–based immunotherapy. Cancer Res; 74(1); 104–18. ©2013 AACR.
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5-fluorouracil, doxorubicin, gemcitabine, and docetaxel reduced circulating myeloid-derived suppressor cells (MDSCs) in mouse models.
“although 5-fluorouracil, doxorubicin, gemcitabine, and docetaxel reduced circulating myeloid-derived suppressor cells (MDSCs) in mouse models [42–45]”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [43]
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- Authors
- Alizadeh, D., Trad, M., Hanke, N. T., Larmonier, C. B., Janikashvili, N., Bonnotte, B., Katsanis, E., & Larmonier, N.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Larmonier, Nicolas
- Venue
- Cancer Research
- Published
- 2014-01-01
- Volume
- 74
- Issue
- 1
- Pages
- 104-118
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3896092
- OpenAlex
- W2143145234
- Cited by
- 416
- References
- 52
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 36 · 2023: 40 · 2022: 43 · 2021: 44 · 2020: 42 · 2019: 25 · 2018: 27 · 2017: 29 · 2016: 32 · 2015: 33 · 2014: 13 · 2013: 1
- FWCI
- 14.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA-023074, R01CA104926, T32CA009213, P30CA023074)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- doxorubicin, myeloid-derived suppressor cells, breast cancer, adoptive T cell therapy, cancer immunotherapy, immunosuppression, natural killer cells, cytotoxic T lymphocytes, perforin and granzyme B, interferon-gamma, Th1 cells, Th17 cells, metastasis
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Breast Neoplasms, Doxorubicin, Female, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Immunotherapy, Adoptive, Myeloid Cells, Cell Line, Tumor, Mice
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