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Pre-fractionation Extends but also Creates a Bias in the Detectable HLA Class ? Ligandome.

ABSTRACT: HLA class ? molecules can communicate a range of cellular alterations (mutations, changes in protein copy number, aberrant post-translational modifications, or pathogen proteins) to CD8+ T lymphocytes in the form of HLA peptide ligands. At any given moment, tens of thousands of different self and foreign HLA class ? peptides may be presented on the cell surface by HLA class ? complexes. Due to the enormous biochemical diversity and low abundance of each of these peptides, HLA ligandome analysis presents unique challenges. Even with advances in enrichment strategies and MS instrumentation and fragmentation, sufficient ligandome depth for identification of viral pathogens and immuno therapeutically important tumor neo-antigens is still not routinely achievable. In this study, we evaluated two pre-fractionation techniques, high-pH reversed-phase and strong cation exchange, for the complementary analyses of HLA class ? peptide ligands. We observe that pre-fractionation substantially extends the detectable HLA class ? ligandome but also creates an identification bias. We thus advocate a rational choice between high-pH reversed-phase or strong cation exchange pre-fractionation for deeper HLA class ? ligandome analysis, depending on the HLA locus, allele, or peptide ligand modification in question.

SUBMITTER: Demmers LC

PROVIDER: S-EPMC6456874 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Pre-fractionation Extends but also Creates a Bias in the Detectable HLA Class Ι Ligandome.

Demmers Laura C LC Heck Albert J R AJR Wu Wei W

Journal of proteome research 20190226 4

HLA class Ι molecules can communicate a range of cellular alterations (mutations, changes in protein copy number, aberrant post-translational modifications, or pathogen proteins) to CD8+ T lymphocytes in the form of HLA peptide ligands. At any given moment, tens of thousands of different self and foreign HLA class Ι peptides may be presented on the cell surface by HLA class Ι complexes. Due to the enormous biochemical diversity and low abundance of each of these peptides, HLA ligandome analysis ...[more]

PMID: 30784271

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Project description:Immune cell infiltrates have proven highly relevant for colorectal carcinoma prognosis, making colorectal cancer a promising candidate for immunotherapy. Because tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here, we comprehensively describe the naturally presented HLA ligandome of colorectal carcinoma and corresponding nonmalignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA class I ligands on colorectal carcinoma and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic colorectal carcinoma-associated pathways, including Wnt, TGFβ, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired colorectal carcinoma and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be overrepresented merely within the colorectal carcinoma ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T-cell repertoire. Overall, these data show that the HLA ligandome reflects cancer-associated pathways implicated in colorectal carcinoma oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived, tumor antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells, might comprise promising candidates for immunotherapeutic applications.Significance: Cancer-associated pathways are reflected in the antigenic landscape of colorectal cancer, suggesting that tumor-specific antigens do not necessarily have to be mutation-derived but may also originate from other alterations in cancer cells. Cancer Res; 78(16); 4627-41. ©2018 AACR.

Dataset Information

Pre-fractionation Extends but also Creates a Bias in the Detectable HLA Class ? Ligandome.

Publications

Pre-fractionation Extends but also Creates a Bias in the Detectable HLA Class Ι Ligandome.

Similar Datasets

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