Doxorubicin Eliminates Myeloid-Derived Suppressor Cells and Enhances the Efficacy of Adoptive T-Cell Transfer in Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 1; pp. 104 - 118
• Main Authors: ALIZADEH, Darya, TRAD, Malika, HANKE, Neale T, LARMONIER, Claire B, JANIKASHVILI, Nona, BONNOTTE, Bernard, KATSANIS, Emmanuel, LARMONIER, Nicolas
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2014
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cell Line, Tumor; Doxorubicin - pharmacology; Female; Gynecology. Andrology. Obstetrics; Humans; Immunotherapy, Adoptive - methods; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - pathology; Pharmacology. Drug treatments; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumors; Antineoplastic agent; DNA topoisomerase (ATP-hydrolysing); Breast disease; Myeloid derived suppressor cell; Enzyme; Treatment efficiency; Enzyme inhibitor; Breast cancer; Topoisomerase II inhibitor; Malignant tumor; Doxorubicin; Adoptive transfer; Mammary gland diseases; Isomerases; T-Lymphocyte; Anthracyclins; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1545

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.