Biomarker of immunotherapy using zoledronate-expanded gamma-delta T cell

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17215
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Izumi Hiroki 国立研究開発法人国立がん研究センター, 東病院, 医員 (80813485)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺癌 / ドライバー遺伝子 / 免疫治療 / γδT細胞

Outline of Final Research Achievements

Expanded Vγ9Vδ2T cells demonstrate tumor cytotoxicity, which was enhanced by ZOL concentrations and Effector/ Target cell ratio. Zoledronate upregulate the expression of HMGCR, one of enzyme in mevalonate pathway, as well as FPP synthase inhibition, resulting in enhancement of Vγ9Vδ2T cell-mediated cytotoxicity. In addition, erlotinib, an EGFR inhibitor also upregulate the expression of HMGCR and FDPS. However, the knockdown of EGFR does not demonstrate synergistic enhancement of Vγ9Vδ2T-mediated cytotoxicity in combination with zoledronate. There seems not to be relationships between types of oncogenic drivers and ZOL-induced Vγ9Vδ2T cell mediated cytotoxicity. It still remains to be clarified which factor is predictive biomarker of Vγ9Vδ2T-utilizing immunotherapy.

Free Research Field

肺癌

Academic Significance and Societal Importance of the Research Achievements

Vγ9Vδ2T細胞による腫瘍細胞の障害活性は、特定のドライバー遺伝子で特に有効であるという結果は見いだせなかったが、ドライバー遺伝子陰性の細胞株と比較して遜色ない細胞障害活性を認めており、ドライバー遺伝子陽性例に対しても効果が期待できる免疫治療の一つであると考えられる。Vγ9Vδ2T細胞を用いた免疫治療の安全性・有効性をドライバー遺伝子陽性例を含む肺癌で検証していくことで、既存の免疫治療（免疫チェックポイント阻害剤）で効果が得られないドライバー遺伝子陽性の肺癌患者にも免疫治療の恩恵が得られる可能性がある。