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Review
. 2024 Sep 5:15:1442783.
doi: 10.3389/fimmu.2024.1442783. eCollection 2024.

Deciphering the HLA-E immunopeptidome with mass spectrometry: an opportunity for universal mRNA vaccines and T-cell-directed immunotherapies

Maya Weitzen #  1 , Mohammad Shahbazy #  2 , Saketh Kapoor  1 , Etienne Caron  1   3
Affiliations
Review

Deciphering the HLA-E immunopeptidome with mass spectrometry: an opportunity for universal mRNA vaccines and T-cell-directed immunotherapies

Maya Weitzen et al. Front Immunol. .

Abstract

Advances in immunotherapy rely on _targeting novel cell surface antigens, including therapeutically relevant peptide fragments presented by HLA molecules, collectively known as the actionable immunopeptidome. Although the immunopeptidome of classical HLA molecules is extensively studied, exploration of the peptide repertoire presented by non-classical HLA-E remains limited. Growing evidence suggests that HLA-E molecules present pathogen-derived and tumor-associated peptides to CD8+ T cells, positioning them as promising _targets for universal immunotherapies due to their minimal polymorphism. This mini-review highlights recent developments in mass spectrometry (MS) technologies for profiling the HLA-E immunopeptidome in various diseases. We discuss the unique features of HLA-E, its expression patterns, stability, and the potential for identifying new therapeutic _targets. Understanding the broad repertoire of actionable peptides presented by HLA-E can lead to innovative treatments for viral and pathogen infections and cancer, leveraging its monomorphic nature for broad therapeutic efficacy.

Keywords: HLA-E peptides; cancer immunotherapy; immunopeptidome; mass spectrometry; vaccine design; viral infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Exploration of HLA-E expression at the RNA and protein levels in human tissues and cell types using the Human Protein Atlas. (A) Expression profiles in human tissues of HLA-E both on the mRNA and protein level. The protein expression data from 44 normal human tissue types is derived from antibody-based protein profiling using conventional and multiplex immunohistochemistry. Each bar represents the highest expression score found in a particular group of tissues. Protein expression scores are based on a best estimate of the “true” protein expression from a knowledge-based annotation, described more in detail under Assays & annotation. The mRNA expression data is derived from RNA-seq from 40 different normal tissue types. RNA expression summary shows the consensus data based on normalized expression (nTPM) values from two different sources: internally generated Human Protein Atlas RNA-seq data and RNA-seq data from the Genotype-Tissue Expression (GTEx) project. (B) RNA expression of HLA-E at the single-cell level. The single-cell RNA sequencing (scRNAseq) data analysis was based on publicly available genome-wide expression data. Twelve out of twenty-six cluster cell types (right) are shown in the legend for simplicity. Use https://www.proteinatlas.org/ENSG00000204592-HLA-E for an in-depth exploration of HLA-E expression across human tissues and cell types. (B) was generated automatically using the Human Protein Atlas (https://www.proteinatlas.org/) (20).
Figure 2
Figure 2
Comparative analysis of the previously reported HLA-E-bound peptides identified by non-MS versus MS-based immunopeptidomics techniques. (A) A two-way Venn diagram showing the overlap between the previously reported HLA-E-bound peptides and the corresponding sequence motif for each dataset. (B) Histogram showing length distribution of the previously reported HLA-E-bound peptides. (C) Histogram showing NetMHCpan 4.1 analysis of the previously reported HLA-E-bound peptides: percentages of predicted Strong Binders (SB); Weak Binders (WB) and Non-Binders (NB) are indicated (71). (D) A three-way Venn diagram comparing MS-identified HLA-E-bound peptides with findings from Joosten et al. (53), a notable non-MS study, and other non-MS studies. (E) A four-way Venn diagram illustrating the overlap among several studies that have characterized or examined higher numbers of HLA-E-bound peptides, including Lampen et al. (55) (MS-based), Joosten et al. (53) (non-MS), and other studies (see also Supplementary Table S1 ). Venn diagrams were generated by https://www.interactivenn.net/ (72). The sequence motifs were generated by Seq2Logo v. 2.0 (https://services.healthtech.dtu.dk/services/Seq2Logo-2.0/) (73) and GibbsCluster v. 2.0 (https://services.healthtech.dtu.dk/services/GibbsCluster-2.0/) (74) software tools. The bar graphs were generated by GraphPad Prism v. 9.3.1.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This article was supported by a startup package provided by Yale University to establish the Caron laboratory.

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