2018 Fiscal Year Final Research Report

Novel target cells in tumor microenvironment of lung cancer: focusing on fibrocytes to overcome drug resistance and develop the innovative therapy

Research Project

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Project/Area Number	16H05309
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Respiratory organ internal medicine
Research Institution	The University of Tokushima
Principal Investigator	NISHIOKA Yasuhiko 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (70274199)
Co-Investigator(Kenkyū-buntansha)	後東久嗣徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (00437641) 西條敦郎徳島大学, 大学院医歯薬学研究部(医学域), 特任助教 (00467812) 荻野広和徳島大学, 大学院医歯薬学研究部(医学域), 助教 (20745294) 埴淵昌毅徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (80335794)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	線維細胞 / 肺がん / 血管新生 / がん幹細胞 / 免疫チェックポイント / がん免疫
Outline of Final Research Achievements	To overcome drug resistance and develop the innovative therapy, the analysis of function of fibrocytes, which were identified to mediate the resistance mechanism for anti-angiogenic agents, were performed in the present study. We found the increased number of fibrocytes in peripheral blood of patients with lung cancer who showed the clinical resistance to anti-angiogenic therapy. In addition, fibrocytes showed the ability to generate stem cell-like phenotype of lung cancer cells in in vitro experiments, indicating the notion that regulating the function of fibrocytes might be critical to inhibit the progression of lung cancer. Immunological analysis showed that fibrocytes had the effects to up- or down-regulate T cell-immunity in vitro. Intra-tumoral administration with fibrocytes, furthermnore, enhanced the anti-tumor activity mediated by anti-PD-1 or anti-PD-L1 antibodies. These results indicate that fibrocytes play an important role in tumor-immunity.
Free Research Field	呼吸器内科学、がん免疫
Academic Significance and Societal Importance of the Research Achievements	本研究結果から線維細胞は肺がん細胞に直接作用して肺がんの腫瘍としての性格を悪い方向（がん幹細胞化）に調節していることが明らかになったことから、線維細胞を標的に治療法の開発研究を行う重要性が高まったと考えられる。血管新生阻害薬に耐性となった肺がん患者の末梢血には線維細胞が増加しており、耐性化のマーカーとなる可能性が示唆された。さらに、血管新生阻害薬と免疫チェックポイント阻害薬の併用効果に線維細胞の作用が関与している新たな可能性が示され、がん免疫療法のメカニズムの理解に繋がる重要な結果が得られたと考えられる。