Role of tumor microenvironment in the chronic infection HTLV-1 and the ATL development

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Kansai Medical University
• Principal Investigator: Fujisawa Jun-ichi 関西医科大学, 医学部, 教授 (40181341)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: HTLV-1 / ヒト化マウス / 白血病 / PD-1 / 免疫チェックポイント / 細胞障害性T細胞 / CADM1

Outline of Final Research Achievements

To examine the role of PD-1/PD-L1 co-inhibitory signaling in ATL development, we analyzed the effect of anti-PD-1 antibody on the leukemic growth of T-cells in HTLV-1 infected humanized mouse, in which the human immune system against HTLV-1 infection is functionally established.
HTLV-1 infection of humanized mice induced hundreds fold increase of CD4 T-cells and most of infected mice died in 2 months, although the number of CD8 T-cells was similarly elevated in parallel with the overgrowth of CD4 T-cells. Administration of anti-PD-1 antibody substantially retarded the increase of CD4 T-cells as well as CD8+ T-cells in PBL and prolonged the survival of infected mice. Since most of CD8 T-cells in the infected mouse was found to be infected with HTLV-1, the co-inhibitory signals induced by the antigen non-specific activation of CD8 T-cells possibly suppress the anti-HTLV-1 immunity and the blocking of PD-1/PD-L1 pathway could have restored the immunity.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

ヒト免疫系が再構築されたヒト化マウスの系で、抗PD-1抗体の投与がHTLV-1感染細胞の腫瘍性増殖を抑制したことから、ヒト化マウスが免疫チェックポイントシグナル制御を介したATL発症予防法の開発に有用な実験系を提供することが示された。また、ヒト化マウス脾臓内において増殖したCD8T細胞の多くにHTLV-1の感染が観察され、抗HTLV-1宿主免疫への影響が示唆されたことから、HTLV-1感染初期のヒトにおけるCD8T細胞のHTLV-1感染、およびその抗HTLV-1宿主免疫ヘの関与に注目することで、ATL発症の初期過程の理解に新たな方向性を与えるものと期待される。