title: Restoration of natural killer cell cytotoxicity by VEGFR-3 inhibition in myelogenous leukemia.
abstract: Acute myeloid leukemia (AML) cells in vivo are constantly exposed to lymphangiogenic cytokines such as VEGF-C. However, it is poorly understood how the VEGF-C signaling modulates the immune functions in the tumor microenvironment. We have previously reported that natural killer (NK) cells in AML patients strongly upregulated VEGFR-3, the major VEGF-C receptor, and that the VEGFR-3 expression level in NK cells inversely correlates with their cytotoxic potential. These findings have led us to hypothesize that VEGFR-3 inhibition may reinstate the cytotoxic capacity of the AML-associated NK cells. To address this hypothesis, we employed a pharmaceutical approach to block the VEGFR-3 function in the murine model of syngeneic myelogenous leukemia. Using various molecular and cellular analyses, we assessed the correlation between VEGFR-3 inhibition and NK cell cytotoxicity. Indeed, we found that leukemic environment is highly enriched with lymphangiogenic stimuli, and that VEGFR-3 inhibition restored NK cell killing function with an increased IFN-γ level, providing a therapeutic implication of VEGFR-3 against AML. Together, we demonstrate the therapeutic value of functional modulation of NK cells by blocking VEGFR-3, and provide a possibility of advanced therapeutic approaches using immune cells against myelogenous leukemia.
authors.affiliation: Cancer Research Institute, Department of Hematology, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Department of Hematology, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sohye
authors.initials: S
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Department of Hematology, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Woo-Sung
authors.initials: WS
authors.lastname: Min
authors.affiliation: Cancer Research Institute, Department of Hematology, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea. Electronic address: cumckim@catholic.ac.kr.
authors.forename: Hee-Je
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: C441602:3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; D007211:Indoles; D009281:Naphthalenes; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Interferon-γ; Leukemia; Natural killer cell; VEGFR-3