2019 年度実施状況報告書

Regulation of oxidative metabolic product-mediated immune suppressive tumor microenvironment to improve the efficacy of immune checkpoint blockade therapy in cancers.

研究課題

研究課題/領域番号	19K16808
研究機関	慶應義塾大学
研究代表者	Sayem MohammadAbu 慶應義塾大学, 医学部(信濃町), 特任助教 (80772920)
研究期間 (年度)	2019-04-01 – 2021-03-31
キーワード	VAP-1 inhibitor / H2O2 / Immunosuppression / CTLs / ICBs
研究実績の概要	Immunosuppression could hinder the induction of cytotoxic T lymphocytes in the tumor cells. Modulation of the immunosuppressive tumor microenvironment is essential for enhancing the anti-tumor efficacy of immune checkpoint blockers. In this study, we determined that the inhibition of vascular adhesion protein 1 using the specific inhibitor U-V296 could reduce the size of tumors, induce anti-tumor T-cells, and synergize with immune checkpoint blockers in an immune dependent manner. These responses can partly be attributed to a reduction in the levels of the pleiotropic signaling molecule H2O2 and the downstream signaling events associated with it, which principally involve reduction in the expressions of IL-4 and other genes related to the Th2/M2-phenotype, angiogenesis, and fibrosis.
現在までの達成度 (区分)	現在までの達成度 (区分) 2: おおむね順調に進展している理由 The project is progressing rather smoothly although there are many variation of the experiments we originally planed. We have completed most of the in vitro and in vivo experiments. We are now focusing on human relevance of our finding. We obtained reasonable data to write a draft manuscript. We hope we can finish our project within due time.
今後の研究の推進方策	We showed that reduction of H2O2 is one of the key mechanisms that cause the improvement of the observed anti-tumor response. To dissect more, we would like to stained the mRNA of various Th1 and Th2 cytokines, other mediators (IFN-g, IL-2, IL-4, IL-13, TGF-β) by RNAScope technology in tumor microenvironment. We will analyze the expression of genes and proteins involved in angiogenesis (Pecam1) and fibrosis (Acta2, Loxl2, a-Sma), transcription factors (Gata3, Irf4 etc) responsible for Th2 or TAMs polarization by qPCR, Western blot and Immunohistochemistry. We also would like to analyze the transcriptome data from our own laboratory and TCGA database to see whether our observed phenomena also exist in human cancers.