Development of anticancer immunoadjuvant therapy against glycolysis
| Project/Area Number |
24501336
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor immunology
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| Research Institution | Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses |
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Principal Investigator |
INOUE Norimitsu 地方独立行政法人大阪府立病院機構大阪府立成人病センター(研究所), 研究所, 部門長 (80252708)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 乳酸 / プロトン / IL-23 / IL-17 / アルギナーゼ１ / ジクロロ酢酸 / がん免疫療法 / 解糖系 / 腫瘍免疫 / Warburg効果 / dichloroacetate / 腫瘍随伴マクロファージ / アルギナーゼ |
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| Outline of Final Research Achievements |
The activation of oncogenic signaling pathways induces the reprogramming of glucose metabolism in tumor cells and increases lactic acid secretion into the tumor microenvironment. Here, we show that lactic anion and acidification increased IL-23/IL-17 pathway and arginase 1 (ARG1) expression, respectively. The IL-23/IL-17 pathway promotes inflammation in the tumor microenvironment. The overexpression of ARG1 inhibits T cell proliferation and activation. We show that dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinases, targets macrophages to suppress activation of the IL-23/IL-17 pathway and the expression of ARG1 by lactic acid. Furthermore, lactic acid-pretreated macrophages inhibited CD8+ T cell proliferation, but CD8+ T cell proliferation was restored when macrophages were pretreated with lactic acid and DCA. DCA increased antitumor immunotherapeutic activity in tumor-bearing mouse models. We would liken to identify lactic anion and proton-responsible factors.
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] A possible abscopal effect of post-irradiation immunotherapy in two patients with metastatic lung tumors.2014
Author(s)
4.Kodama, K., Higashiyama, M., Okami, J., Tokunaga, T., Fujiwara, A., Inoue, N., Akazawa, T. and Seya, T.
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Journal Title
In. Canc. Conf. J.
Volume: 3
Issue: 2
Pages: 122-127
DOI
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Peer Reviewed / Open Access
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[Journal Article] Production of canine soluble CD40 ligand to induce maturation of monocyte derived dendritic cells for cancer immunotherapy.2013
Author(s)
Wijewardana, V., Sugiura, K., Yahata, M., Akazawa, T., Wijesekera, D. P., Imamoto, S., Hatoya, S., Inoue, N., Inaba, T.
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Journal Title
Vet. Immunol. Immunopathol.
Volume: 156
Issue: 1-2
Pages: 121-127
DOI
Related Report
Peer Reviewed
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[Journal Article] Dichroloacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity2013
Author(s)
Ohashi, T., Akazawa, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., Inoue, N.
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Journal Title
Int. J. Cancer
Volume: 133
Issue: 5
Pages: 1107-1118
DOI
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Peer Reviewed
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[Presentation] Dichloroacetate acts on myeloid cells to suppress IL-23/IL-17 pathway activation and arginase 1 expression caused by tumor-secreted lactic acid2013
Author(s)
Inoue, N., Ohashi, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., Akazawa, T.
Organizer
Tumor metabolism meets Immunology
Place of Presentation
Thon-Dittmer Palais (Regensburg, Germany)
Related Report
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[Presentation] Improvement of dendritic cell-based immunotherapy for enhancing systemic immune responses against cancer2013
Author(s)
Wijewardana, V., Sugiura, K., Akazawa, T., Wijesekera, D. P. H., Imamoto, S., Inoue, N., Inaba, T.
Organizer
第42回日本免疫学会学術集会
Place of Presentation
幕張メッセ（千葉県千葉市）
Related Report
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[Book] Handbook of Glycosyltransferases and Related Genes, Glycosylphosphatidylinositol- N-acetylglucosaminyltransferase (GPI-GlcNAc transferase): A complex comprised of PIGA, PIGC, PIGH, PIGQ, PIGP, PIGY and DPM2.2014
Author(s)
Kinoshita, T., Inoue, N., Murakami, Y.
Total Pages
1707
Publisher
Springer Japan
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