Dataset Information

T cells of colorectal cancer patients’ stimulated by neoantigenic and cryptic peptides better recognize autologous tumor cells

ABSTRACT: Immunopeptidome analysis of patient-derived colorectal cancer cell lines HROC113 and HROC285 T0 M2 from the HROC collection [Mullins et al. Cancers (Basel). 2019;11(10):1520. doi: 10.3390/cancers11101520] was performed to characterize the natural HLA class I presented ligandome in native as well as IFNγ treated cells.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Markus Löffler

LAB HEAD: Hans-Georg Rammensee

PROVIDER: PXD037587 | Pride | 2023-03-11

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	171219_MG_HROC113_IFNy_W6_DDA_Rep1_400-650mz_msms36.raw	Raw
	171219_MG_HROC113_IFNy_W6_DDA_Rep1_400-650mz_msms36.raw.md5	Raw
	171219_MG_HROC113_IFNy_W6_DDA_Rep2_400-650mz_msms37.raw	Raw
	171219_MG_HROC113_IFNy_W6_DDA_Rep2_400-650mz_msms37.raw.md5	Raw
	171219_MG_HROC113_IFNy_W6_DDA_Rep3_400-650mz_msms38.raw	Raw

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T cells of colorectal cancer patients' stimulated by neoantigenic and cryptic peptides better recognize autologous tumor cells.

Schwarz Sandra S Schmitz Johanna J Löffler Markus W MW Ghosh Michael M Rammensee Hans-Georg HG Olshvang Evgenia E Markel Marvin M Mockel-Tenbrinck Nadine N Dzionek Andrzej A Krake Susann S Arslan Basak B Kampe Kapil Dev KD Wendt Anne A Bauer Peter P Mullins Christina S CS Schlosser Andreas A Linnebacher Michael M

Journal for immunotherapy of cancer 20221201 12

<h4>Background</h4>Patients with cancers that exhibit extraordinarily high somatic mutation numbers are ideal candidates for immunotherapy and enable identifying tumor-specific peptides through stimulation of tumor-reactive T cells (Tc).<h4>Methods</h4>Colorectal cancers (CRC) HROC113 and HROC285 were selected based on high TMB, microsatellite instability and HLA class I expression. Their HLA ligandome was characterized using mass spectrometry, compared with the HLA ligand atlas and HLA class I- ...[more]

PMID: 36460334

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Project description:Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from non-canonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the presentation and immunogenicity of nonC antigens across different cancer types to better understand their contribution to cancer immunosurveillance and to address whether they could be exploited therapeutically. To this end, we employed a proteogenomics pipeline to identify nonC HLA-I ligands derived from off-frame translation of coding sequences and non-coding regions (UTR, ncRNA, intronic and intergenic) in patient-derived tumor cell lines (TCL) of different histological types (4 gynecological cancer, 3 melanoma and 2 head and neck cancer patients). First, peptides bound to HLA-I were isolated and analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) using state-of-the-art procedures. Amino acid (Aa) sequences were identified through the previously described pipeline Peptide-PRISM, with some modifications. Briefly, for each MS spectrum, the top 10 candidates were first identified by de novo sequencing and later mapped to a database including the 3-frame transcriptome and 6-frame genome. Additionally, whole-exome sequencing (WES) information of each TCL was included to interrogate the presentation of mutated peptides derived cancer-specific NSM. The false-discovery rate (FDR) was calculated independently for each category considering the search space and peptide length in a stratified mixture model as previously described. Next, in order to select nonC peptides preferentially presented by tumor cells, immunopeptidomics data from several healthy tissues and samples available from the HLA ligand atlas was used to filter out peptides presented in healthy tissues. To overcome a potential bias toward frequent alleles, the peptides were excluded at the ORF level rather than the Aa sequence. As a result, we found that from a total of 839 unique nonC peptides detected in our tumor samples, 38.5% were predicted to derive from ORFs also present in healthy tissue (nonC-HL). Hence, 61.6% (n=517) were considered preferentially presented on tumor HLA-I, referred to as non-canonical tumor ligands (nonC-TL). Out results showed that, although nonC-TL constitued the most abundant source of candidate tumor antigens, as compared to neoantigens, cancer-germline or melanoma-associated antigens, pre-existing antitumor T cells in cancer patients preferentially recognized neoantigens rather than nonC-TL. Nonetehless, nonC-TL elicited de novo T-cell responses via in vitro sensitization of donor lymphocytes. We identified TCRs specific to three nonC-TL, two of which mapped to the 5’ UTR regions of HOXC13 and ZKSCAN1, and one mapping to a non-coding spliced variant of the C5orf22C. These immunogenic nonC-TL were expressed across tumor types but were barely or not detected in healthy cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they are attractive novel targets for widely applicable immunotherapies.