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HLA-I peptidomics od Meningioma tissues - Peptide length distribution and multiple specificity in naturally presented HLA-I ligands

ABSTRACT: HLA-I molecules bind short peptides and present them to CD8+ T cells for TCR recognition. The length of HLA-I ligands typically ranges from 8 to 12 amino acids, but high variability is observed between different alleles. Here we used recent HLA peptidomics data to analyze in an unbiased way peptide length distributions over 85 different HLA-I alleles. Our results revealed clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to unravel some of the molecular basis of peptide length distributions and predict peptide length distributions based on HLA-I sequences only. We further took advantage of our collection of curated HLA peptidomics studies to investigate multiple specificity in HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distributions and multiple specificity significantly improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on ten newly generated HLA peptidomics datasets from meningioma samples.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Meningioma Cell

DISEASE(S): Meningioma

SUBMITTER: Michal Bassani-Sternberg

LAB HEAD: Michal Bassani-Sternberg

PROVIDER: PXD009925 | Pride | 2019-07-31

REPOSITORIES: Pride

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			Action	DRS
	20171130_QEh1_LC1_HLAIp_SA_JMI_3779-AMM_R1.raw	Raw
	20171130_QEh1_LC1_HLAIp_SA_JMI_3779-AMM_R2.raw	Raw
	20171130_QEh1_LC1_HLAIp_SA_JMI_3795-BMT_R1.raw	Raw
	20171130_QEh1_LC1_HLAIp_SA_JMI_3795-BMT_R2.raw	Raw
	20171130_QEh1_LC1_HLAIp_SA_JMI_3803-RE_R1.raw	Raw

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Project description:Background: Patient derived organoids (PDOs) can be established from colorectal cancers as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFN) or MEK-inhibitors. Methods: Four PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analysed by MS. Results: We identified an average of 9,936 unique peptides per PDO which compares favourably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. Treatment of four PDOs with IFN upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFN-inducible genes. HLA class II presented peptides increased on average 16-fold with IFN treatment. MEK-inhibitor treatment showed no consistent effect on class I or II HLA expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Conclusions: Only 3 out of 612 non-synonymous mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.

Dataset Information

HLA-I peptidomics od Meningioma tissues - Peptide length distribution and multiple specificity in naturally presented HLA-I ligands

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