T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery
Cetin M, Pinamonti V, Schmid T, et al. Science Advances 2024
Abstract
Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA–presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and thera- peutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and tar- gets physiologically processed and presented by an individual’s unmanipulated, complete human leukocyte anti- gen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multi- ple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER’s potency and versatility.
H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient
Boschert T, Kromer K, Lerner T, et al. Science Advances 2024
Abstract
H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)–restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II–restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.
Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy
Tan CL, et al. Nature Biotechnology 2024
Abstract
The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR identifies tumor-reactive TCRs in TILs from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity and sensitivity (geometric mean) from 0.38 to 0.74. By predicting tumor-reactive TCRs in a matter of days, TCR clonotypes can be prioritized to accelerate the manufacture of personalized T cell therapies.
- Taga Lerner
- Theresa Shmid
- Ana Mellado Fuentes
- Claudia Maldonado
- Georgios Samaras
- Kieran Didi
- Marlene Ganslmeier
- Tsu-Yang Chao
- Constantin Diekmann
- Yonatan Herzig
- Jing Zhang
- Kristina Kromer
- Laura Fisch
- Miguel Hernandez
- Valeriia Dragan
- Miray Cetin
- Veronica Pinamonti
- Nina Papavasiliou
- Michael Platten
- Ed Green
- Tamara Boschert
- Nathan Felix
- Frederik Stevenaert
- Arlette Kouwenhoven
- Murray McKinnon
- Jercen Van Houdt
- Viggo Van Tendeloo
Career Path
2023 – current: Head of Immunology Discover and Head of Research USA
2018 – 2023: BioMed X Group Leader
2014 – 2018: Postdoc, Novartis Institutes for Biomedical Research, Basel, Switzerland
2013 – 2014: Postdoc, Freiburg Institute of Advanced Studies, Freiburg, Germany
2007 – 2013: PhD, University of Freiburg, Germany
Acknowledgements
2023 – current: Head of Immunology Discover and Head of Research USA
2018 – 2023: BioMed X Group Leader
2014 – 2018: Postdoc, Novartis Institutes for Biomedical Research, Basel, Switzerland
2013 – 2014: Postdoc, Freiburg Institute of Advanced Studies, Freiburg, Germany
2007 – 2013: PhD, University of Freiburg, Germany
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