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Front. Immunol. | doi: 10.3389/fimmu.2018.02697

Specific MHC-I Peptides are Induced using PROTACs

  • 1AbbVie (United States), United States

Peptides presented by the class-I major histocompatibility complex (MHC-I) are important targets for immunotherapy. The identification of these peptide targets greatly facilitates the generation of T-cell-based therapeutics. Herein, we report the capability of proteolysis targeting chimera (PROTAC) compounds to induce the presentation of specific MHC class-I peptides derived from endogenous cellular proteins. Using LC-MS/MS, we identified several BET-derived MHC-I peptides induced by treatment with three BET-directed PROTAC compounds. To understand our ability to tune this process, we measured the relative rate of presentation of these peptides under varying treatment conditions using label-free mass spectrometry quantification. We found that the rate of peptide presentation reflected the rate of protein degradation, indicating a direct relationship between PROTAC treatment and peptide presentation. We additionally analyzed the effect of PROTAC treatment on the entire immunopeptidome and found many new peptides that were displayed in a PROTAC-specific fashion: we determined that these identifications map to the BET pathway, as well as potential off-target or unique-to-PROTAC pathways. This work represents the first evidence of the use of PROTAC compounds to induce the presentation of MHC-I peptides from endogenous cellular proteins, highlighting the capability of PROTAC compounds for the discovery and generation of new targets for immunotherapy.

Keywords: Immunopeptidome, Degradome, PROTAC (proteolysis-targeting chimeric molecule), Mass spectrometry - LC-MS/MS, JQ1(+), a BET-specific bromodomain inhibitor, Immunotherapy, MHC class I antigen, HLA class I

Received: 27 Aug 2018; Accepted: 01 Nov 2018.

Edited by:

Christian Kurts, Universität Bonn, Germany

Reviewed by:

Loredana Saveanu, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Alessio Ciulli, School of Life Sciences, University of Dundee, United Kingdom  

Copyright: © 2018 Jensen, Potts, Ready and Patterson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Melanie J. Patterson, AbbVie (United States), North Chicago, United States, melanie.patterson@abbvie.com