Isolation of T cell receptor specifically reactive with autologous tumour cells from tumour-infiltrating lymphocytes and construction of T cell receptor engineered T cells for esophageal squamous cell carcinoma

作者：Qin Tan, Chaoting Zhang, Wenjun Yang, Ying Liu, Heyilimu Palashati, Dongdong Feng, Liying Xing, Ke Yang, Zheming Lu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2019 · DOI：10.1186/s40425-019-0709-7 · 被引用次数：27 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Monoclonal and Polyclonal Antibodies Research

BACKGROUND: T cell receptor-engineered T cells (TCR-Ts) therapy is a promising cancer treatment strategy. Nowadays, most studies focused on identification of high-avidity T cell receptors (TCRs) directed against neoantigens derived from somatic mutations. However, few neoantigens per patient could induce immune response in epithelial cancer and additionally many tumor-specific antigens could be derived from noncoding region. Autologous tumor cells (ATCs) could be unbiased stimulators in activating and enriching tumor-reactive T cells. However, it's unknown if T cells engineered to express TCRs isolated from tumor-reactive T cells enriched by ATCs have strong antitumor response. METHODS: In this study, multiple TIL fragments obtained from a patient with esophageal squamous cell carcinoma (ESCC) were screened for specific recognition of ATCs. Tumor-reactive TILs were enriched by in vitro repeated stimulation of ATCs and isolated based on CD137 upregulation. Subsequently, tumor-reactive TCR was obtained by single-cell RT-PCR analysis and was introduced into peripheral blood lymphocytes to generate TCR-Ts. RESULTS: T cells from pre- and post-stimulated TIL-F1 co-cultured with ATCs, and identified their most dominant TCR. This TCR was introduced into PBLs to generate TCR-Ts, which specifically identified and killed ATCs in vivo and in vitro. CONCLUSION: This strategy provides the means to generate tumor-reactive TCR-Ts for ESCC, which is especially important for patients without p...