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The Immunogenicity of a Proline-Substituted Altered Peptide The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability This information is current as of September 25, 2021. Ida Hafstrand, Elien M. Doorduijn, Renhua Sun, Anna Talyzina, Marjolein Sluijter, Sara Pellegrino, Tatyana Sandalova, Adil Doganay Duru, Thorbald van Hall and Adnane Achour J Immunol 2018; 200:2860-2868; Prepublished online 5 Downloaded from March 2018; doi: 10.4049/jimmunol.1700228 http://www.jimmunol.org/content/200/8/2860 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/03/03/jimmunol.170022 Material 8.DCSupplemental References This article cites 52 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/200/8/2860.full#ref-list-1 by guest on September 25, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability Ida Hafstrand,*,† Elien M. Doorduijn,‡ Renhua Sun,*,† Anna Talyzina,*,† Marjolein Sluijter,‡ Sara Pellegrino,x Tatyana Sandalova,*,† Adil Doganay Duru,{,‖ Thorbald van Hall,‡,1 and Adnane Achour*,†,1 Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell–based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)–based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that Downloaded from is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2Db in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2Db/Trh4. Comparison of the crystal structures of the H-2Db/Trh4-p3P http://www.jimmunol.org/ and H-2Db/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur–p interactions with H-2Db residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability. The Journal of Immunology, 2018, 200: 2860–2868. ajor histocompatibility complex class I downregu- Ag presentation machinery, including TAP-, tapasin-, and by guest on September 25, 2021 lation represents a significant challenge for suc- proteasome-deficient cancer cells (4–10). Our studies also M cessful T cell–based cancer immunotherapy. Indeed, revealed the existence of a broad unique TEIPP-specific T cell immunotherapy studies in melanoma patients have previously repertoire that is highly specific to only Ag presentation ma- demonstrated that progression of cancer lesions is linked to chinery–deficient cancer cells (5, 8, 10). These TEIPP-specific reduced MHC class I (MHC-I)/peptide cell surface expression, T cells are selected in the thymus, egress with a naive pheno- whereas cancer lesions with normal expression regressed in the type, and can be efficiently exploited for immunotherapy same patient (1–3). We have previously demonstrated the ex- against immune-escaped, TAP-deficient tumor cells expressing istence of a new class of hidden MHC-I–presented self-peptides, low levels of MHC-I/peptide complexes (5). However, priming termed T cell epitope associated with impaired peptide pro- of these TEIPP-specific T cells is required through exposition to cessing (TEIPP), that only appear in tumor cells with defective APCs with normal MHC-I expression (11). *Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, T.S., and A.A., the modified epitope and produced it; I.H., E.M.D., A.D.D., and T.S. 17165 Stockholm, Sweden; †Department of Infectious Diseases, Karolinska Univer- performed all the structural and biophysical work presented within this manuscript; sity Hospital, Solna, 17176 Stockholm, Sweden; ‡Medical Oncology, Leiden Univer- R.S. gathered diffraction data, contributed to solving the crystal structure, and con- sity Medical Center, 2333 ZA Leiden, the Netherlands; xDepartment of tributed to the design of figures and the redaction of the manuscript; A.T. performed Pharmaceutical Science, General and Organic Chemistry Section, University of and analyzed all of the molecular dynamic simulations assays; and T.v.H. designed Milan, 20133 Milan, Italy; {Cell Therapy Institute, Nova Southeastern University, experiments in mice that M.S. and E.M.D. performed. Fort Lauderdale, FL 33314; and ‖College of Allopathic Medicine, Nova Southeastern The crystal structure presented in this article has been submitted to the Protein Data University, Fort Lauderdale, FL 33328 Bank (http://www.rcsb.org/pdb/home/home.do) under accession code 5MZM. 1 A.A. and T.v.H. contributed equally to this work. Address correspondence and reprint requests to Adnane Achour or Thorbald van ORCIDs: 0000-0002-1012-9532 (I.H.); 0000-0002-8203-4946 (R.S.); 0000-0001- Hall, Science for Life Laboratory, Department of Medicine Solna, Karolinska Insti- 9727-7441 (A.T.); 0000-0002-2325-3583 (S.P.); 0000-0002-7694-6420 (T.S.); tutet, Tomtebodava¨gen 23, Box 1031, 17121 Solna, 17165 Stockholm, Sweden (A.A.) 0000-0002-9115-558X (T.v.H.); 0000-0003-0432-710X (A.A.). or Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands (T.v.H.). E-mail addresses: [email protected] (A.A.) or Received for publication February 14, 2017. Accepted for publication February 7, [email protected] (T.v.H.) 2018. The online version of this article contains supplemental material. This work was supported by the Swedish Research Council (to A.A.), the Swedish Cancer Society (to A.A.), and by Dutch Cancer Society Grant UL 2010-4785 (to T.v.H.). Abbreviations used in this article: MFI, mean fluorescence intensity; MHC-I, MHC The funders had no role in study design, data collection and analysis, decision to class I; TEIPP, T cell epitope associated with impaired peptide processing; tg, trans- publish, or preparation of the manuscript. genic; Tm, melting temperature. I.H., T.S., and A.A. wrote the initial draft of the manuscript that was complemented Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 by contributions from T.v.H., A.D.D., and E.M.D.; S.P. designed, together with I.H., www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700228 The Journal of Immunology 2861 We have also recently determined the crystal structure of H-2Db Ags, although much more immunogenic, the H-2Db/Trh4-p3P in complex with the first prototypic TEIPP peptide Trh4 (12). The complex was clearly less stable on the cell surface as well as in structure revealed that the peptide takes a noncanonical peptide- solution compared with the wild-type H-2Db/Thr4 complex. Thus, binding pattern forming extensive sulfur–p interactions that con- our results stand in contrast to the present notion that higher im- tribute to the overall complex stability. Indeed, in contrast to all munogenicity is directly linked to higher MHC/peptide complex previously reported crystal structures of H-2Db epitopes, the stability (19), and they indicate that rigidification of the altered TEIPP peptide Trh4 (MCLRMTAVM), derived from the com- peptide ligand combined with absolute molecular mimicry com- monly expressed cellular protein Trh4 (10, 13), does not contain pared with the wild-type neoantigen are key for enhanced TCR an asparagine at position 5 and comprises an unusually large recognition. Collectively, our results extend our earlier findings on number of sulfur-containing residues at positions 1, 2, 5, and 9. p3P-exchanged peptide epitopes to TEIPP-directed CTL responses The crystal structure of H-2Db/Trh4 combined with site-directed for
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