Dataset Information

Multifactorial Remodeling of the Cancer Immunopeptidome by IFNγ.

ABSTRACT: IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We performed proteomic analyses of untreated and IFNγ-treated colorectal cancer patient-derived organoids and combined this with transcriptomic and HLA-I immunopeptidomics data to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNγ. IFNγ-induced changes in the abundance of source proteins, switching from the constitutive to the immunoproteasome, and differential upregulation of different HLA alleles explained some, but not all, observed peptide abundance changes. By selecting for peptides which increased or decreased the most in abundance, but originated from proteins with limited abundance changes, we discovered that the amino acid composition of presented peptides also influences whether a peptide is upregulated or downregulated on HLA-I through IFNγ. The presence of proline within the peptide core was most strongly associated with peptide downregulation. This was validated in an independent dataset. Proline substitution in relevant core positions did not influence the predicted HLA-I binding affinity or stability, indicating that proline effects on peptide processing may be most relevant. Understanding the multiple factors that influence the abundance of peptides presented on HLA-I in the absence or presence of IFNγ is important to identify the best targets for antigen-specific cancer immunotherapies such as vaccines or T-cell receptor engineered therapeutics.

Significance

IFNγ remodels the HLA-I-presented immunopeptidome. We showed that peptide-specific factors influence whether a peptide is upregulated or downregulated and identified a preferential loss or downregulation of those with proline near the peptide center. This will help selecting immunotherapy target antigens which are consistently presented by cancer cells.

SUBMITTER: Newey A

PROVIDER: S-EPMC10655636 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multifactorial Remodeling of the Cancer Immunopeptidome by IFNγ.

Newey Alice A Yu Lu L Barber Louise J LJ Choudhary Jyoti S JS Bassani-Sternberg Michal M Gerlinger Marco M

Cancer research communications 20231101 11

IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We performed proteomic analyses of untreated and IFNγ-treated colorectal cancer patient-derived organoids and combined this with transcriptomic and HLA-I immunopeptidomics data to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNγ. IFNγ-induced changes in the abundance of source proteins, switching from the ...[more]

PMID: 37991387

Similar Datasets

Project description:Peptide vaccination remains a viable approach to induce T-cell mediated killing of tumors. To identify potential T-cell targets for Triple-Negative Breast Cancer (TNBC) vaccination, we examined the effect of the pro-inflammatory cytokine interferon-γ (IFNγ) on the transcriptome, proteome, and immunopeptidome of the TNBC cell line MDA-MB-231. Using high resolution mass spectrometry, we identified a total of 84,131 peptides from 9,647 source proteins presented by human leukocyte antigen (HLA)-I and HLA-II alleles. Treatment with IFNγ resulted in a remarkable remolding of the immunopeptidome, with only a 34% overlap between untreated and treated cells across the HLA-I immunopeptidome, and expression of HLA-II only detected on treated cells. IFNγ increased the overall number, diversity, and abundance of peptides contained within the immunopeptidome, as well increasing the coverage of individual source antigens. The suite of peptides displayed under conditions of IFNγ treatment included many known tumor associated antigens, with the HLA-II repertoire sampling 17 breast cancer associated antigens absent from those sampled by HLA-I molecules. Quantitative analysis of the transcriptome (10,248 transcripts) and proteome (6,783 proteins) of these cells revealed 229 common proteins and transcripts that were differentially expressed. Most of these represented downstream targets of IFNγ signaling including components of the antigen processing machinery such as tapasin and HLA molecules. However, these changes in protein expression did not explain the dramatic modulation of the immunopeptidome following IFNγ treatment. These results demonstrate the high degree of plasticity in the immunopeptidome of TNBC cells following cytokine stimulation and provide evidence that under pro-inflammatory conditions a greater variety of potential HLA-I and HLA-II vaccine targets are unveiled to the immune system. This has important implications for the development of personalized cancer vaccination strategies.

Project description:The prevalence of gastric cancer is associated with several factors including geographical location, diet, and genetic background of the host. However, it is evident that infection with Helicobacter pylori (H. pylori) is crucial for the development of the disease. Virulence of the bacteria is also important in modulating the risk of the disease. After infection, H. pylori gains access to the gastric mucosa and triggers the production of cytokines that promote recruitment of inflammatory cells, probably involved in tissue damage. Once the infection is established, a cascade of inflammatory steps associated with changes in the gastric epithelia that may lead to cancer is triggered. H. pylori-induced gastritis and H. pylori-associated gastric cancer have been the focus of extensive research aiming to discover the underlying mechanisms of gastric tissue damage. This research has led to the association of host genetic components with the risk of the disease. Among these is the presence of single nucleotide polymorphisms (SNPs) in several genes, including cytokine genes, which are able to differentially modulate the production of inflammatory cytokines and then modulate the risk of gastric cancer. Interestingly, the frequency of some of these SNPs is different among populations and may serve as a predictive factor for gastric cancer risk within that specific population. However, the role played by other genetic modifications should not be minimized. Methylation of gene promoters has been recognized as a major mechanism of gene expression regulation without changing the primary structure of the DNA. Most DNA methylation occurs in cytosine residues in CpG dinucleotide, but it can also be found in other DNA bases. DNA methyltransferases add methyl groups to the CpG dinucleotide, and when this methylation level is too high, the gene expression is turned off. In H. pylori infection as well as in gastric cancer, hypermethylation of promoters of genes involved in cell cycle control, metabolism of essential nutrients, and production of inflammatory mediators, among others, has been described. Interestingly, DNA changes like SNPs or mutations can create CpG sites in sequences where transcription factors normally sit, affecting transcription.In this chapter, we review the literature about the role of SNPs and methylation on H. pylori infection and gastric cancer, with big emphasis to the H. pylori role in the development of the disease due to the strong association between both.

Dataset Information

Multifactorial Remodeling of the Cancer Immunopeptidome by IFNγ.

Significance

Publications

Multifactorial Remodeling of the Cancer Immunopeptidome by IFNγ.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets