| 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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| 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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