2023 Fiscal Year Final Research Report

In vivo comprehensive genome editing analysis to elucidate the mechanisms of cancer refractoriness for development of novel therapies

Research Project

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Project/Area Number	22K19554
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research Institution	Tokyo Medical and Dental University
Principal Investigator	Tanaka Shinji 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420)
Co-Investigator(Kenkyū-buntansha)	新部彩乃 (樺嶋彩乃) 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20445448) 島田周東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20609705) 秋山好光東京医科歯科大学, 大学院医歯学総合研究科, 講師 (80262187)
Project Period (FY)	2022-06-30 – 2024-03-31
Keywords	ゲノム編集 / 難治性がん / 転移 / エピゲノム制御 / 細胞外基質 / CAR-T / 樹状細胞 / 免疫疲弊
Outline of Final Research Achievements	Using in vivo comprehensive genome editing analysis of pancreatic cancer lines derived from C57BL/6 mice, we found that a group of genes related to the antigen presentation mechanism and extracellular matrix (ECM) contributed to the acquisition of metastatic potential in the same strain of mice. We found epigenomic regulation of the antigen-presenting machinery, which may be a potential therapeutic target. Furthermore, we found that ECM signaling and ECM enzyme inhibitors activate dendritic cells with T cells, and prolong prognosis with suppression of metastasis. We performed in vivo comprehensive genome editing analysis to identify immune-related genes in a mouse model of MSLN+ pancreatic cancer and generated a new CAR vector with additional immune activating genes. The analysis of the therapeutic efficacy of New CAR-T cell therapy revealed the importance of dendritic cell activation, and furthermore, the efficacy was enhanced by the combination of immune exhaustion inhibitors.
Free Research Field	消化器外科学
Academic Significance and Societal Importance of the Research Achievements	近年のゲノム編集技術の開発によって大きな技術革新が生まれており、治療開発への応用が期待されている。申請者は高効率多重ゲノム編集技術を開発し、初代培養細胞およびCAR-T細胞へ同時に複数の遺伝子変異を導入する革新的手法に成功した。本研究では、高効率ゲノム編集技術をin vivo CRISPR/Cas9 sgRNA library導入へ応用し、膵癌細胞の網羅的ゲノム編集解析により転移能獲得機序を解明し、CAR-T細胞の網羅的ゲノム編集解析により膵癌組織への免疫浸潤機序を解明する。免疫応答モデルを用いて癌細胞および免疫細胞の両面から膵癌の難治性機序を明らかにし、新規治療法を開拓する挑戦的課題である。