To extend the useful immunopeptidome, Kacen and Javitt et al. established a pipeline (PROMISE) to identify the common post-translational modifications from mass spec data of HLA class I-eluted peptides. Analysis of the position of modifications demonstrated effects on peptide:HLA interaction, supported by modeling and binding data, including elucidation of new binding motifs, particularly involving modified cysteines. Some modification occurred in presumptive TCR recognition regions. Analysis of immunopeptidome data from a set of breast cancer tissues revealed potentially therapeutically useful tumor-specific changes, such as phosphorylation and cysteinylation.
Contributed by Ed Fritsch
ABSTRACT: Post-translational modification (PTM) of antigens provides an additional source of specificities targeted by immune responses to tumors or pathogens, but identifying antigen PTMs and assessing their role in shaping the immunopeptidome is challenging. Here we describe the Protein Modification Integrated Search Engine (PROMISE), an antigen discovery pipeline that enables the analysis of 29 different PTM combinations from multiple clinical cohorts and cell lines. We expanded the antigen landscape, uncovering human leukocyte antigen class I binding motifs defined by specific PTMs with haplotype-specific binding preferences and revealing disease-specific modified targets, including thousands of new cancer-specific antigens that can be shared between patients and across cancer types. Furthermore, we uncovered a subset of modified peptides that are specific to cancer tissue and driven by post-translational changes that occurred in the tumor proteome. Our findings highlight principles of PTM-driven antigenicity, which may have broad implications for T cell-mediated therapies in cancer and beyond.
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Immuno
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem, Israel. (6) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (8) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (9) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (10) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (11) Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. (12) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (13) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (14) Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem, Israel. (15) De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. (16) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. (17) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. yifat.merbl@weizmann.ac.il.
