Dataset Information

Discovery of Non-Canonical Peptides Derived from Novel Small Open Reading Frames as MHC-I Epitopes

ABSTRACT: Immunopeptides that are translated in cells and presented at the cell surface by major histocompatibility complex (MHC) mole-cules are important epitopes in basic Immunology and translational cancer immunotherapy. While most of the reported immuno-peptides are derived from protein coding sequence, the non-canonical peptides translated from “non-coding” regions are emerging and have attracted much attention in recent years. However, sensitive and accurate identification of such peptides remains a challenging task. Here we report an optimized approach integrating Ribo-seq and mass spectrometry to identify hundreds of non-canonical MHC-binding peptides. Three pipelines for analyzing Ribo-seq data were compared to generate small open reading frame (sORF) databases. Meanwhile, we have also combined bottom-up and de novo searching in proteomics data analysis and identified more immunopeptides. 7902 canonical and 308 non-canonical immunopeptides have been identified with selected ones vigorously validated. The present study provides a handy solution for identifying non-canonical MHC epitopes. The novel im-munopeptides resolving mechanisms of cancer antigen presentation, as well as applications in cancer immunotherapies.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Jurkat Cell

SUBMITTER: Yuanliang Zhang

LAB HEAD: Zhao Qian

PROVIDER: PXD024415 | Pride | 2021-11-03

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20201009_ORF_database.fasta	Fasta
	HCT.SRX2189157_SRX2189159_SRX569214.fdr01_PRICE_.fasta	Fasta
	HCT116_PRICE.zip	Other
	HCT116_riboTISH.zip	Other
	HCT116_sORF.zip	Other

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Publications

An Integrated Approach for Discovering Noncanonical MHC-I Peptides Encoded by Small Open Reading Frames.

Chen Lei L Zhang Yuanliang Y Yang Ying Y Yang Yang Y Li Huihui H Dong Xuan X Wang Hongwei H Xie Zhi Z Zhao Qian Q

Journal of the American Society for Mass Spectrometry 20210714 9

MHC-I peptides are a group of important immunopeptides presented by major histocompatibility complex (MHC) on the cell surface for immune recognition. The majority of reported MHC-I peptides are derived from protein coding sequences, and noncanonical peptides translated from small open reading frames (sORF) are largely unknown due to the lack of accurate and sensitive detection methods. Herein we report an efficient approach that implements complementary bioinformatic strategies to improve the i ...[more]

PMID: 34260243

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Project description:All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) can convey non-self antigens derived from pathogens or mutations to amount T-cell responses. Alterations in tumor-specific antigens – particularly mutation-bearing peptides (neoantigens) presented by MHC — can serve as potent substrates for anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring interferon gamma (IFN-γ) induced alterations to antigen presentation, using a lymphoma cell line. IFN-γ treatment resulted in a set of differentially expressed proteins (2 % of all quantified proteins) including components of antigen presentation machinery or interferon signaling pathways. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells antigen repertoires. Accordingly, by surveying immunopeptides, distinct peptide repertoires were exclusively observed in the IFN-γ induced samples. Furthermore, an additional set of presented peptides distinguished control and the IFN-γ samples by their altered relative abundances including neoantigens. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance should help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.