Comprehensive detection of high affinity TCRs specific for HTLV-1

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22783
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Sugata Kenji 熊本大学, ヒトレトロウイルス学共同研究センター, 特定事業研究員 (10650616)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: HTLV-1 / 高親和性T細胞受容体(TCR) / 成人T細胞白血病(ATL) / HTLV－1関連脊髄症(HAM) / HLA class-I / CD8 T細胞 / 次世代シークエンス解析

Outline of Final Research Achievements

Recent studies have shown effectiveness and feasibility of adaptive transfer therapies for treatment of patients with cancers. In this study, we focused on high affinity TCRs (eligible for the therapies) specific for HTLV-1 antigen based on single cell analysis data from HTLV-1 patients. HLA-I restricted TCRs from CD8 T cells, which expanded in TCR repertoire, were transduced into primary T cells. Using cytokine production assay, we detected that the cloned TCRs can recognize HLA-A24:02-restricted Tax301-309 on antigen presenting cells. Furthermore, we found that the HTLV-1 specific TCRs were frequently detected from PBMCs and cerebrospinal fluid of HAM patients. On the other hand, CD8 T cells derived from ATL patients did not show the specific response against HLA-A24/Tax complexes, suggesting that HLA-A24/Tax specific CD8 T cells might affect ATL onset in HTLV-1 carriers. We are ongoing further analysis of the Tax specific TCRs focusing affinity of TCR-peptide/MHC complex.

Free Research Field

がん免疫

Academic Significance and Societal Importance of the Research Achievements

ATLに対しては化学療法やヒト化CCR4抗体などの治療法が試みられているものの、有効な治療法が見つかっていない。近年、がん患者に対して腫瘍抗原T細胞を使用した移入療法が効果をあげている。申請者は高親和性HTLV-1特異的TCRの探索を行い、HAM患者検体から7種類のHLA-A*24:02拘束性Tax301-309特異的TCRを検出した。HLA-A24陽性ATLでの優位に増加しているCD8T細胞クローンではそれらの特異的T細胞を検出できなかったことから、それらの特異的T細胞がATLの発症に寄与している可能性が示唆された。現在、得られたTCRの解析を進めるとともに特許申請を視野に研究進めている。