期刊
BLOOD
卷 132, 期 18, 页码 1911-1921出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-04-843763
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资金
- Broad Institute
- Broad Next10 Seed funding
- National Institutes of Health, National Cancer Institute [1RO1CA155010-02, T32CA207021, R50RCA211482A, R21 CA216772]
- National Institutes of Health, National Heart, Lung, and Blood Institute [5R01HL103532-03]
- DFCI Center for Cancer Immunotherapy Research fellowship
- Howard Hughes Medical Institute Medical Research Fellowship
- American Society of Hematology HONORS Award
- PhRMA Fellowship for Translational Medicine and Therapeutics
- National Cancer Institute-Specialized Programs of Research Excellence (SPORE) [2P50CA10194211A1]
- NATIONAL CANCER INSTITUTE [T32CA207021, R50CA211482, R21CA220147, R21CA216772, R01CA155010] Funding Source: NIH RePORTER
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 TCRa and TCRb, 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 viralantigen- 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 neoantigenprediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise to an immunogenic neoantigen mut-MGA, and use this approach to identify the mut-MGA-specific TCR sequence. This approach provides a means to identify and express TCRs, and then rapidly assess antigen specificity and functional avidity of a reconstructed TCR, which can be applied for monitoring antigenspecific T-cell responses, and potentially for guiding the design of effective T-cell-based immunotherapies.
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