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Surface expression of mutated HLA peptide (KIF2C - P13L) in lymphoma, melanoma and LCL cell lines

ABSTRACT: The abundance of the mutated peptide KIF2C (P13L; peptide sequence: RLFLGLAIK) on peptide-pulsed (0.1 and 1µM) versus transgenic minigene-expressing cell lines (U698M, A2058, Mel15 LCL) was assessed using HLA class I immunoprecipitation followed by mass spectrometry analysis of the HLA peptides.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Melanoma,Lymphoma

SUBMITTER: Piero Giansanti

LAB HEAD: Piero Giansanti

PROVIDER: PXD051734 | Pride | 2024-10-31

REPOSITORIES: Pride

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			Action	DRS
	Ecl1_0362_R0113-01_S006149_L_W01_LFQ_02.raw	Raw
	Ecl1_0362_R0113-01_S006150_L_W01_LFQ_02.raw	Raw
	Ecl1_0362_R0113-01_S006151_L_W01_LFQ_02.raw	Raw
	Ecl1_0362_R0113-01_S006152_L_W01_LFQ_02.raw	Raw
	Ecl1_0362_R0113-01_S006153_L_W01_LFQ_02.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.

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Surface expression of mutated HLA peptide (KIF2C - P13L) in lymphoma, melanoma and LCL cell lines

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