title: Targeting Ornithine Decarboxylase by α-Difluoromethylornithine Inhibits Tumor Growth by Impairing Myeloid-Derived Suppressor Cells.
abstract: α-Difluoromethylornithine (DFMO) is currently used in chemopreventive regimens primarily for its conventional direct anticarcinogenesic activity. However, little is known about the effect of ornithine decarboxylase (ODC) inhibition by DFMO on antitumor immune responses. We showed in this study that pharmacologic blockade of ODC by DFMO inhibited tumor growth in intact immunocompetent mice, but abrogated in the immunodeficient Rag1(-/-) mice, suggesting that antitumor effect of DFMO is dependent on the induction of adaptive antitumor T cell immune responses. Depletion of CD8(+) T cells impeded the tumor-inhibiting advantage of DFMO. Moreover, DFMO treatment enhanced antitumor CD8(+) T cell infiltration and IFN-γ production and augmented the efficacy of adoptive T cell therapy. Importantly, DFMO impaired Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs) suppressive activity through at least two mechanisms, including reducing arginase expression and activity and inhibiting the CD39/CD73-mediated pathway. MDSCs were one primary cellular target of DFMO as indicated by both adoptive transfer and MDSC-depletion analyses. Our findings establish a new role of ODC inhibition by DFMO as a viable and effective immunological adjunct in effective cancer treatment, thereby adding to the growing list of chemoimmunotherapeutic applications of these agents.
authors.affiliation: Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and.
authors.forename: Cong
authors.identifier: http://orcid.org/0000-0001-5478-7361
authors.initials: C
authors.lastname: Ye
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Hubei Maternity and Child Health Hospital, Wuhan 430070, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Geng
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Donye
authors.identifier: http://orcid.org/0000-0002-4413-9376
authors.initials: D
authors.lastname: Dominguez
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Siqi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Lei
authors.identifier: http://orcid.org/0000-0002-5951-1425
authors.initials: L
authors.lastname: Qin
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Alan
authors.initials: A
authors.lastname: Long
authors.affiliation: Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
authors.affiliation: Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bin.zhang@northwestern.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000518:Eflornithine / Q000494:pharmacology*; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology*; D009955:Ornithine Decarboxylase / Q000276:immunology*; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase; D000518:Eflornithine