title: Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis.
abstract: Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor-derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment.
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Insu
authors.initials: I
authors.lastname: Jeon
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Hyungseok
authors.initials: H
authors.lastname: Seo
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Boyeong
authors.initials: B
authors.lastname: Song
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Kyoo-A
authors.initials: KA
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Yongwoo
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea. cykang@snu.ac.kr.
authors.forename: Chang-Yuil
authors.initials: CY
authors.lastname: Kang
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D018960:Hyaluronan Receptors / Q000502:physiology; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D038042:Myelopoiesis; D009374:Neoplasms, Experimental / Q000276:immunology*; D053495:Osteopontin / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology
chemical_list: D019496:Cancer Vaccines; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D053495:Osteopontin; D048049:Extracellular Signal-Regulated MAP Kinases