Dataset Information

Identification of tumor antigens in the HLA peptidome of patient-derived xenograft tumors in mouse

ABSTRACT: Personalized cancer immunotherapy targeting patient-specific cancer/testis (CTA) antigens and neoantigens may benefit from large-scale tumor HLA peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. While significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This work attempted to overcome some of these obstacles by using patient-derived xenograft tumors (PDX) in mice as the tissue sources for HLA peptidome analysis. PDX tumor provide a proxy for expansion of the patient tumor by re-grafting them through several passages to immune compromised mice. The HLA peptidomes of human biopsies were compared to those derived from PDX tumors. Larger HLA peptidomes were obtained from the significantly larger PDX tumors as compared to the patient biopsies. The HLA peptidomes of different PDX tumors derived from the same source tumor biopsy were very reproducible, even following subsequent passages to new naïve mice. A large number of CTA-derived HLA peptides were discovered, as well as several neoantigens. Taken together, use of PDX tumors for HLA peptidome analysis serves as a highly expandable and stable source of reproducible and authentic peptidomes, opening up new opportunities for defining large HLA peptidomes when only small tumor biopsies are available. This approach provides a large source for tumor antigens identification potentially useful for personalized immunotherapy.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Bladder Carcinoma,Lung Cancer,Vascular Cancer,Neck Carcinoma,Pancreas Adenocarcinoma,Head And Neck Squamous Cell Carcinoma,Cholangiocarcinoma,Stomach Carcinoma

SUBMITTER: Nataly Rijensky

LAB HEAD: Arie Admon

PROVIDER: PXD016060 | Pride | 2020-05-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	46722-46723474054813948523P1HBandPDXhumanexomemousedatabasesMQ1.5.8.3.zip	Other
	48140-48141P3HBandPDXhumanexomemousedatabasesMQ1.5.8.3.zip	Other
	48144-48145P4HBandPDXhumanexomemousedatabasesMQ1.5.8.3.zip	Other
	48515-48516P5HBandPDXhumanexomemousedatabasesMQ1.5.8.3.zip	Other
	48519-48520P7HBandPDXhumanexomemousedatabasesMQ1.5.8.3.zip	Other

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Publications

Identification of Tumor Antigens in the HLA Peptidome of Patient-derived Xenograft Tumors in Mouse.

Rijensky Nataly Mancette NM Blondheim Shraga Netta R NR Barnea Eilon E Peled Nir N Rosenbaum Eli E Popovtzer Aron A Stemmer Solomon M SM Livoff Alejandro A Shlapobersky Mark M Moskovits Neta N Perry Dafna D Rubin Eitan E Haviv Itzhak I Admon Arie A

Molecular & cellular proteomics : MCP 20200525 8

Personalized cancer immunotherapy targeting patient-specific cancer/testis antigens (CTA) and neoantigens may benefit from large-scale tumor human leukocyte antigen (HLA) peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. Although significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This w ...[more]

PMID: 32451349

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Project description:Treatment of cancer cells with anti-cancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumorâs gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anti-cancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited anti-tumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug. The transcriptomes, proteomes and HLA peptidomes of the U-87, T98G and LNT-229 GBM human cell lines were analyzed before and after treatment with Decitabine. Overall, the RNA-Seq transcriptome analyses resulted in the identification of above 26000 transcripts, the proteome analyses identified about 7500 proteins and the HLA class I peptidome analyses resulted in above 25000 identified HLA peptides. Two biological repetitions of the transcriptome, three of the proteome and three of the HLA peptidome were performed with each of the cell lines and treatment, resulting in highly reproducible datasets.