Deciphering mechanisms of immune escape by single-cell barcoding

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21542
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Nagoya University
• Principal Investigator: Hinohara Kunihiko 名古屋大学, 医学系研究科, 特任准教授 (50549467)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: 養子免疫療法 / 薬剤耐性 / 発現型バーコード / １細胞RNAシーケンス / 空間トランスクリプトーム解析

Outline of Final Research Achievements

Most human tumors are composed of genetically and phenotypically heterogeneous cancer cell populations that pose a major challenge for the clinical management of cancer patients. Here we used mouse model of adoptive T cell transfer (ACT) to investigate the impact of tumor heterogeneity on therapy effectiveness. We found that all tumors underwent regressions after transfer of tumor antigen-specific cytotoxic T cells but eventually some tumors re-start to grow. We observed that resistance can occur either by selection of pre-existing mERK2-negative clones or via evolution from initially mERK2-positive drug-sensitive cells. Also, we developed single-cell lineage tracing system using expressed DNA barcoding technology to further understand evolutionary trajectory of drug-resistant cancer cells. By utilizing this experimental system, we will identify key roles for intratumor heterogeneity and tumor evolution in ACT response.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

治療抵抗性の獲得メカニズムに異なるパターンが存在するということは、それぞれのメカニズムに対して異なる治療アプローチが必要であることを意味している。例えば養子免疫療法に加えて、先天的耐性細胞を狙い撃ちする薬剤と後天的耐性獲得を抑制する薬剤の３者をコンビネーションで投与する治療法などが効果的であることを示している。今後これらの耐性細胞の特徴を明らかにし、効果的な治療薬の開発へと結びつけたい。