Development of anticancer immunoadjuvant therapy against glycolysis

2014 Fiscal Year Final Research Report

• Project/Area Number: 24501336
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses
• 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)
• Project Period (FY): 2012-04-01 – 2015-03-31
• 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

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.

Free Research Field

腫瘍免疫と代謝