Solving an MHC allele–specific bias in the reported immunopeptidome

Klatt, Martin G.; Mack, Kyeara N.; Bai, Yang; Aretz, Zita E.H.; Nathan, Levy; Mun, Sung Soo; Dao, Tao; Scheinberg, David A.

doi:10.1172/jci.insight.141264

Cited by 20 publications

(28 citation statements)

References 27 publications

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“…Chemical labeling has also been shown to increase the number of peptide identifications but may potentially change the overall allele representation in the sample ( 19 ). Furthermore, a recent study suggests that higher concentrations of ACN during peptide elution and desalting could enable detection of more hydrophobic and immunogenic peptides missed in current sample preparation approaches ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Optimized Liquid and Gas Phase Fractionation Increases HLA-Peptidome Coverage for Primary Cell and Tissue Samples

Klaeger

Apffel

Clauser

et al. 2021

Molecular & Cellular Proteomics

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Please cite this article as: RRH: Optimized MS approach for increased HLA-peptide coverage This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 99%

Optimized Liquid and Gas Phase Fractionation Increases HLA-Peptidome Coverage for Primary Cell and Tissue Samples

Klaeger

Apffel

Clauser

et al. 2021

Molecular & Cellular Proteomics

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“…Harvested cells were pelleted and washed 3 times in ice-cold sterile PBS (Gibco, Cat 10010–0230.) Immunoprecipitation, HLA ligand separation and LC-MS/MS were performed as previously described [ 20 ]. Briefly, cells were lysed in 7.5 mL of 1% CHAPS (MilliporeSigma) for 1 hour at 4°C, lysates were spun down for 1 hour with 20,000 g at 4°C, and supernatant fluids were isolated.…”

Section: Methodsmentioning

confidence: 99%

A TCR mimic monoclonal antibody for the HPV-16 E7-epitope p11-19/HLA-A*02:01 complex

et al. 2022

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More effective treatments are needed for human papilloma virus (HPV)-induced cancers despite HPV virus vaccination. The oncogenic HPV protein targets are currently undruggable and intracellular and therefore there are no antibodies to these targets. Here we report the discovery of TCR mimic monoclonal antibodies (TCRm mAb) specific for the HPV E7 protein p11-19, YMLDLQPET, when presented on the cell surface in the context of HLA-A*02:01 by use of human phage display libraries. One of the mAbs, 3F8, was able to specifically mediate T cell- redirected cytotoxicity, in a bispecific T cell engager (BiTE) form. While further studies are required to assess the therapeutic potential of this approach, the study provided the proof of concept that TCRm mAb could be a therapeutic strategy for HPV-induced human cancers.

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“…HLA class I ligands (HLA-A, B and -C) and HLA class II ligands (HLA-DR) were isolated as described previously 39 . In brief, 40 mg of Cyanogen bromide-activated-Sepharose 4B (Sigma-Aldrich, cat.…”

Section: Methodsmentioning

confidence: 99%

Unmasking the cryptic immunopeptidome of EZH2 mutated diffuse large B-cell lymphomas through combination drug treatment

Bourne

Mun

Dao

et al. 2021

Preprint

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Exploring the repertoire of peptides presented on major histocompatibility complexes (MHC) has been utilized to identify targets for immunotherapy in many hematological malignancies. However, such data have not been described systematically for diffuse large B-cell lymphomas (DLBCL), which might be explained by the profound downregulation of MHC expression in many DLBCLs, and in particular in the EZH2-mutated subgroup. Epigenetic drug treatment, especially in the context of interferon gamma (IFNg), restored MHC expression in DLBCL. DLBCL MHC-presented peptides were identified via mass spectrometry following tazemetostat or decitabine treatments alone, or in combination with IFNg. Such treatment synergistically increased MHC class I surface protein expression up to 50-fold and class II expression up to 3-fold. Peptides presented on MHC complexes increased to a similar extent for MHC class I and remained constant for class II. Overall, these treatments restored the diversity of the immunopeptidome to levels described in healthy B cells and allowed the systematic search for new targets for immunotherapy. Consequently, we identified multiple MHC ligands from regulator of G protein signaling 13 (RGS13) and E2F transcription factor 8 (E2F8) on different MHC alleles, none of which have been described in healthy tissues and therefore represent tumor-specific MHC ligands, which are unmasked only after drug treatment. Overall, our results show that EZH2 inhibition in combination with decitabine and IFNg can expand the repertoire of MHC ligands presented on DLBCLs by revealing cryptic epitopes, thus allowing the systematic analysis and identification of new potential immunotherapy targets.

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Solving an MHC allele–specific bias in the reported immunopeptidome

Cited by 20 publications

References 27 publications

Optimized Liquid and Gas Phase Fractionation Increases HLA-Peptidome Coverage for Primary Cell and Tissue Samples

Optimized Liquid and Gas Phase Fractionation Increases HLA-Peptidome Coverage for Primary Cell and Tissue Samples

A TCR mimic monoclonal antibody for the HPV-16 E7-epitope p11-19/HLA-A*02:01 complex

Unmasking the cryptic immunopeptidome of EZH2 mutated diffuse large B-cell lymphomas through combination drug treatment

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