Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems

Yosuke Yokota, Hiroyuki Inoue, Yumiko Matsumura, Haruka Nabeta, Megumi Narusawa, Ayumi Watanabe, Chika Sakamoto, Yasuki Hijikata, Mutsunori Iga-Murahashi, Koichi Takayama, Fumiyuki Sasaki, Yoichi Nakanishi, Takehiko Yokomizo, Kenzaburo Tani

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14 Citations (Scopus)

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 CD44hiCD4+ 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.

Original languageEnglish
Pages (from-to)3444-3454
Number of pages11
JournalBlood
Volume120
Issue number17
DOIs
Publication statusPublished - Oct 25 2012

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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