Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors

Assaf Kacen, Aaron Javitt, Matthias P. Kramer, David Morgenstern, Tomer Tsaban, Merav D. Shmueli, Guo Ci Teo, Felipe da Veiga Leprevost, Eilon Barnea, Fengchao Yu, Arie Admon, Lea Eisenbach, Yardena Samuels, Ora Schueler-Furman, Yishai Levin, Alexey I. Nesvizhskii, Yifat Merbl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageAmerican English
Pages (from-to)239-251
Number of pages13
JournalNature Biotechnology
Volume41
Issue number2
DOIs
StatePublished - Feb 2023

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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