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Tumor-associated peptides can be detected from the plasma-derived soluble immunopeptidome in human hepatocellular carcinoma patients – A pre-clinical study on the correlation of the soluble and hepatocellular carcinoma-derived membranous immunopeptidomes.

ABSTRACT: Abstract Background and aims. Hepatocellular carcinoma (HCC) shows limited response to checkpoint inhibitors, leaving opportunity for antigen-based immunotherapy and improved disease monitoring. This study evaluates plasma-derived soluble HLA-I (sHLA-I) peptidome as a minimally invasive source of tumor antigens by comparing them to tumor and adjacent tissue HLA ligands to assess its value for personalized treatment and diagnostics in HCC. Methods. Plasma-derived soluble HLA-I complexes and membranous HLA-I ligands from paired tumor and adjacent liver tissues of HCC and non-HCC control patients were isolated using pan-HLA-I immunoprecipitation and analyzed by LC-MS/MS. Peptide identification and patient-specific HLA binding predictions were complemented by annotation of tumor-associated antigens (TAAs) to compare ligand repertoires across HLA sources. Results The plasma soluble HLA-I (sHLA-I) peptidome from HCC and non-HCC patients was successfully characterized, with 1,553 to 9,421 unique peptides identified per sample after contaminant filtering. Peptides were enriched for canonical 8–11-mer lengths, with most predicted to bind patient-specific HLA-I alleles. Among 3,907 source proteins delivering peptides to the HCC sHLA-I peptidome, 815 were unique to HCC patients, and protein interaction analysis revealed significantly increased network connectivity centered around tumor-associated proteins. Comparison with membranous HLA-I (mHLA-I) peptidomes from tumor and adjacent tissues yielded 20 peptides from 17 tumor-associated antigens (TAAs) that were shared between sHLA-I and mHLA-I. Nine of these were only identified from HCC plasma and not from non-HCC controls, five overlapped with tumor mHLA-I. Conclusions. This pilot study demonstrates that the plasma-derived soluble HLA-I immunopeptidome in HCC patients contains peptides derived from TAAs, at least partially reflective of those presented on tumor tissue. These findings support the potential of sHLA-I profiling as a minimally invasive strategy for identifying actionable targets and tumor-specific signatures in HCC. Future improvements in analytical sensitivity and throughput, and validation in larger cohorts are now needed to establish its clinical utility.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Adult Hepatocellular Carcinoma

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD066255 | Pride | 2025-10-15

REPOSITORIES: Pride

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			Action	DRS
	2047_L_MdB_6jan2020_MdB031.raw	Raw
	2047_L_MdB_6jan2020_MdB031_20200107003149.raw	Raw
	2047_L_MdB_6jan2020_MdB037_HCC.raw	Raw
	2047_L_MdB_6jan2020_MdB037_HCC_20200108041530.raw	Raw
	2047_L_MdB_6jan2020_MdB037_distant.raw	Raw

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Dataset Information

Tumor-associated peptides can be detected from the plasma-derived soluble immunopeptidome in human hepatocellular carcinoma patients – A pre-clinical study on the correlation of the soluble and hepatocellular carcinoma-derived membranous immunopeptidomes.

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