Instruction of tumor microenvironment by NRF2-addicted cancers

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04799
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Tohoku University
• Principal Investigator: Motohashi Hozumi 東北大学, 加齢医学研究所, 教授 (00282351)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: NRF2活性化がん / 代謝物 / 超硫黄分子 / 免疫抑制

Outline of Final Research Achievements

Immunohistological analysis was performed on 90 surgical specimens of untreated lung adenocarcinoma to stratify them into two groups: NRF2-positive and negative cases. Immunohistological and single cell-RNA-seq analyses were performed using antibodies against marker proteins of various immunocompetent cells to examine the types of cells infiltrating the tumor and differences in gene expression in each cell. Reanalysis of data from bulk RNA-seq analysis and single cell-RNA-seq analysis of lung adenocarcinoma stored in public databases showed that infiltration and intratumor differentiation of some immune　cells were suppressed in NRF2-positive cases. Metabolite analysis was performed using mouse carcinoma models and human surgical specimens and found that superdulfides were increased in NRF2-activated tumors.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

本研究から、免疫担当細胞が、癌細胞から分泌される超硫黄分子により機能抑制を受けることが示唆された。解析を進める中で、腫瘍微小環境の中でNRF2活性化がんが放出するグルタチオンパースルフィドが、免疫担当細胞の作用で無機超硫黄分子に変換されるという仮説、すなわち、癌細胞と免疫担当細胞による超硫黄分子リモデリングというユニークな仮説を持つに至った。これは、がん細胞と免疫担当細胞の協調がもたらす代謝変化による新たな腫瘍免疫制御機構であり、新たな治療標的を提示するもの期待できる。