A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens.

Blood
Zhuting HuCatherine J Wu

Abstract

Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent antitumor immune responses and provide strong motivation for improving our understanding of antigen-T-cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRα and TCRβ, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs. We developed a streamlined approach for matching TCR sequences with cognate antigen through on-demand cloning and expression of TCRs and screening against candidate antigens. Here, we first demonstrate the system's capacity to identify viral-antigen-specific TCRs and compare the functional avidity of TCRs specific for a given antigen target. We then apply this system to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs. Furthermore, we use a neoantigen-prediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise ...Continue Reading

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Citations

Nov 6, 2018·Blood·Krishna V Komanduri
May 29, 2019·The Cancer Journal·Melinda A BiernackiMarie Bleakley
Mar 3, 2020·Frontiers in Immunology·Vladimir RoudkoNina Bhardwaj
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May 8, 2020·JCI Insight·Melinda A BiernackiMarie Bleakley
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