癌症研究
T细胞受体
T细胞
髓系白血病
卵巢癌
CD8型
生物
白血病
细胞毒性T细胞
贪婪
髓样
免疫学
癌症
抗原
体外
免疫系统
生物化学
遗传学
作者
Rosa van Amerongen,Renate S. Hagedoorn,Dennis F. G. Remst,Danique C Assendelft,Dirk M. van der Steen,Anne K. Wouters,Marian van de Meent,Michel G.D. Kester,Arnoud H. de Ru,Marieke Griffioen,Peter A. van Veelen,J.H. Frederik Falkenburg,Mirjam H. M. Heemskerk
标识
DOI:10.1136/jitc-2021-004409
摘要
Background Transcription factor Wilms’ tumor gene 1 (WT1) is an ideal tumor target based on its expression in a wide range of tumors, low-level expression in normal tissues and promoting role in cancer progression. In clinical trials, WT1 is targeted using peptide-based or dendritic cell-based vaccines and T-cell receptor (TCR)-based therapies. Antitumor reactivities were reported, but T-cell reactivity is hampered by self-tolerance to WT1 and limited number of WT1 peptides, which were thus far selected based on HLA peptide binding algorithms. Methods In this study, we have overcome both limitations by searching in the allogeneic T-cell repertoire of healthy donors for high-avidity WT1-specific T cells, specific for WT1 peptides derived from the HLA class I associated ligandome of primary leukemia and ovarian carcinoma samples. Results Using broad panels of malignant cells and healthy cell subsets, T-cell clones were selected that demonstrated potent and specific anti-WT1 T-cell reactivity against five of the eight newly identified WT1 peptides. Notably, T-cell clones for WT1 peptides previously used in clinical trials lacked reactivity against tumor cells, suggesting limited processing and presentation of these peptides. The TCR sequences of four T-cell clones were analyzed and TCR gene transfer into CD8+ T cells installed antitumor reactivity against WT1-expressing solid tumor cell lines, primary acute myeloid leukemia (AML) blasts, and ovarian carcinoma patient samples. Conclusions Our approach resulted in a set of naturally expressed WT1 peptides and four TCRs that are promising candidates for TCR gene transfer strategies in patients with WT1-expressing tumors, including AML and ovarian carcinoma.
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