Single-cell derived tumor organoids display diversity in HLA class I peptide presentation
Demmers, Laura C; Kretzschmar, Kai; Van Hoeck, Arne; Bar-Epraïm, Yotam E; van den Toorn, Henk W P; Koomen, Mandy; van Son, Gijs; van Gorp, Joost; Pronk, Apollo; Smakman, Niels; Cuppen, Edwin; Clevers, Hans; Heck, Albert J R; Wu, Wei
(2020) Nature Communications, volume 11, issue 1, pp. 1 - 10
(Article)
Abstract
Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the
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same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15-25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.
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Keywords: Antigen Presentation, Cell Line, Tumor, Clone Cells/immunology, Colorectal Neoplasms/immunology, HLA Antigens/metabolism, Humans, Ligands, Models, Biological, Neoplasm Proteins/metabolism, Organoids/immunology, Proteome/metabolism, Signal Transduction, Single-Cell Analysis, TOR Serine-Threonine Kinases/metabolism, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The authors would like to acknowledge support for this research through the Horizon 2020 program INFRAIA project Epic-XS (Project 823839) and the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019) embedded in the Netherlands Proteomics Centre. L.C.D. and A.J.R.H. are further supported by the NWO Gravitation program Institute for Chemical Immunology (ICI00003). This work was supported by the European Research Council (Advanced Grant ERC-AdG 67013-Organoid to H.C.) and a VENI grant from the Netherlands Organisation for Scientific Research (NWO-ZonMW, 016.166.140 to K.K.). K.K. is a long-term fellow of the Human Frontier Science Program Organization (HFSPO, LT771/2015). We acknowledge Dr. Stefan Stevanović (University of Tubingen, Germany) for providing the pan-HLA antibody W6/32, and thank the USEQ for sequencing support and the UBEC for bioinformatical support. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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