title: Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems.
abstract: BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4(+) T subsets and increasing numbers of Th17 and memory CD44(hi)CD4(+) T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4(+) T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF-induced antitumor memory CD4(+) T cells.
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yokota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Haruka
authors.initials: H
authors.lastname: Nabeta
authors.forename: Megumi
authors.initials: M
authors.lastname: Narusawa
authors.forename: Ayumi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Chika
authors.initials: C
authors.lastname: Sakamoto
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Hijikata
authors.forename: Mutsunori
authors.initials: M
authors.lastname: Iga-Murahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sasaki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D007156:Immunologic Memory; D007942:Leukemia, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor