title: Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer.
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.
authors.affiliation: Authors' Affiliations: Cancer Biology Graduate Program; Arizona Cancer Center; Department of Pediatrics, College of Medicine; Department of Immunobiology, University of Arizona, Tucson, Arizona; Faculty of Medicine, Dijon, and INSERM UMR 1098, Besancon; and Service de Médecine Interne et Immunologie Clinique, CHU Bocage, Dijon, France.
authors.forename: Darya
authors.initials: D
authors.lastname: Alizadeh
authors.forename: Malika
authors.initials: M
authors.lastname: Trad
authors.forename: Neale T
authors.initials: NT
authors.lastname: Hanke
authors.forename: Claire B
authors.initials: CB
authors.lastname: Larmonier
authors.forename: Nona
authors.initials: N
authors.lastname: Janikashvili
authors.forename: Bernard
authors.initials: B
authors.lastname: Bonnotte
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Katsanis
authors.forename: Nicolas
authors.initials: N
authors.lastname: Larmonier
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin