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

Research output: Contribution to journalArticle

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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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Immunologic Memory
Leukotriene B4
Immune system
Granulocyte-Macrophage Colony-Stimulating Factor
Tumors
Immune System
Data storage equipment
T-cells
Neoplasms
T-Lymphocytes
Dendritic Cells
Leukotriene B4 Receptors
Cytophagocytosis
Immunology
Cancer Vaccines
Adoptive Transfer
Chemotactic Factors
Adaptive Immunity
Neoplasm Antigens
Allergy and Immunology

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems. / Yokota, Yosuke; Inoue, Hiroyuki; Matsumura, Yumiko; Nabeta, Haruka; Narusawa, Megumi; Watanabe, Ayumi; Sakamoto, Chika; Hijikata, Yasuki; Iga-Murahashi, Mutsunori; Takayama, Koichi; Sasaki, Fumiyuki; Nakanishi, Yoichi; Yokomizo, Takehiko; Tani, Kenzaburo.

In: Blood, Vol. 120, No. 17, 25.10.2012, p. 3444-3454.

Research output: Contribution to journalArticle

Yokota, Y, Inoue, H, Matsumura, Y, Nabeta, H, Narusawa, M, Watanabe, A, Sakamoto, C, Hijikata, Y, Iga-Murahashi, M, Takayama, K, Sasaki, F, Nakanishi, Y, Yokomizo, T & Tani, K 2012, 'Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems', Blood, vol. 120, no. 17, pp. 3444-3454. https://doi.org/10.1182/blood-2011-10-383240
Yokota, Yosuke ; Inoue, Hiroyuki ; Matsumura, Yumiko ; Nabeta, Haruka ; Narusawa, Megumi ; Watanabe, Ayumi ; Sakamoto, Chika ; Hijikata, Yasuki ; Iga-Murahashi, Mutsunori ; Takayama, Koichi ; Sasaki, Fumiyuki ; Nakanishi, Yoichi ; Yokomizo, Takehiko ; Tani, Kenzaburo. / Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems. In: Blood. 2012 ; Vol. 120, No. 17. pp. 3444-3454.
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AU - Nabeta, Haruka

AU - Narusawa, Megumi

AU - Watanabe, Ayumi

AU - Sakamoto, Chika

AU - Hijikata, Yasuki

AU - Iga-Murahashi, Mutsunori

AU - Takayama, Koichi

AU - Sasaki, Fumiyuki

AU - Nakanishi, Yoichi

AU - Yokomizo, Takehiko

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