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Published January 29, 2019 | Supplemental Material + Accepted Version
Journal Article Open

T cell antigen discovery via trogocytosis


T cell receptor (TCR) ligand discovery is essential for understanding and manipulating immune responses to tumors. We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that present cognate peptide–major histocompatibility complex (MHC) molecules. Co-incubation of T cells expressing an orphan TCR with target cells collectively presenting a library of peptide–MHCs led to specific labeling of cognate target cells, enabling isolation of these target cells and sequencing of the cognate TCR ligand. We validated this method for two clinically employed TCRs and further used the platform to identify the cognate neoepitope for a subject-derived neoantigen-specific TCR. Thus, target cell trogocytosis is a robust tool for TCR ligand discovery that will be useful for studying basic tumor immunology and identifying new targets for immunotherapy.

Additional Information

© 2019 Springer Nature Publishing AG. Received 29 June 2018; Accepted 13 December 2018; Published 28 January 2019. Data availability: The original NGS DNA-seq data have been deposited in the Sequence Read Archive under accession numbers SRR8217181, SRR8217182 and SRR8217183. The data that support the findings of this study are available from the corresponding author upon request. Source data for Figs. 2, 4 and 5 are available online. We thank I. Antoshechkin (Millard and Muriel Jacobs Genetics and Genomics Laboratory, Caltech) for deep DNA sequencing, and D. Perez, J. Tijerina and R.A. Diamond (Flow Cytometry Facility, Caltech) for cell sorting. This work was supported by the Prostate Cancer Foundation Challenge Award 15CHAL02 to D.B., O.N.W., L.Y. and M.T.B., and the National Cancer Institute (grant 1U54 CA199090-01 to J.R.H.). M.T.B. is the recipient of a Jane Coffin Childs Postdoctoral Fellowship. A.R. was supported by National Institutes of Health (NIH) grant R35 CA197633. G.L. was supported by the Parker Institute for Cancer Immunotherapy. J.T.K. was supported by NIH/National Center for Advancing Translational Science UCLA CTSI grant KL2TR001882. Author Contributions: M.T.B. conceived of the approach. G.L. and M.T.B. designed research. G.L., M.T.B., S.W., A.V.J., M.T.L., J.K.W., J.T.K., Y.S., Y.L. and D.C. performed experiments. S.P., J.M.Z., A.R. and J.R.H. provided critical reagents and analyzed results. O.N.W. analyzed results. G.L., M.T.B. and D.B. analyzed results and wrote the paper. Competing interests: M.T.B., G.L., J.T.K., S.W. and D.B. are co-inventors on a patent application concerning the described technology, which is licensed to PACT Pharma, Inc. J.R.H. and A.R. are directors and consultants of PACT; D.B. is a consultant of PACT and head of their scientific advisory board; M.T.B. and S.P. are employees of PACT; J.M.Z. is a consultant of PACT; and each of the foregoing individuals has equity interests in PACT.

Attached Files

Accepted Version - nihms-1037677.pdf

Supplemental Material - 41592_2018_305_Fig10_ESM.jpg

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Supplemental Material - 41592_2018_305_MOESM1_ESM.pdf

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Additional details

August 22, 2023
October 19, 2023