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The soluble HLA repertoire captures neoantigenic, cryptic, and tumour-associated peptides in melanoma.

Melanoma research just scored a win for peptide science. Australian scientists cracked open the “soluble HLA” (sHLA) repertoire and found it loaded with neoantigenic, cryptic, and tumor-associated peptides—straight from patient blood plasma, not just tumor biopsies. This is big: plasma sampling is a lot less invasive than chasing down tumor tissue, and it could open new doors for tracking and understanding cancer in real time.

Mol Cell Proteomics

by Goncalves G, Conway JW, Shamekhi T et al.

“The soluble HLA repertoire captures neoantigenic, cryptic, and tumour-associated peptides in melanoma. Goncalves G(1), Conway JW(2), Shamekhi T(3), Steele JR(4), Beckwith J(2), Blundell SA(4), Tanuwidjaya E(1), Schittenhelm RB(4), Long GV(5), Pires da Silva I(6), Faridi P(7). Author information: (1)Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia; Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia. (2)Melanoma Institute Australia, The University of Sydney, Wollstonecraft, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia. (3)Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia. (4)Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia. (5)Melanoma Institute Australia, The University of Sydney, Wollstonecraft, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia; Mater Hospital, North Sydney, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia. (6)Melanoma Institute Australia, The University of Sydney, Wollstonecraft, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia; Champalimaud Foundation, Lisbon, Portugal. (7)Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia; Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia. Electronic address: Pouya.Faridi@monash.edu. Melanoma is a highly immunogenic malignancy in which T cell recognition of HLA-presented peptides plays a central role in tumour control. While immunopeptidomics has enabled detailed characterisation of melanoma antigen repertoires, its clinical application is limited by restricted access to tumour tissue. Soluble HLA (sHLA) complexes in circulation present a potential minimally invasive alternative. However, the extent to which circulating HLA repertoires reflect tumour-derived antigen presentation remains unclear. Here, we applied an optimised SAPrIm workflow coupled with Orbitrap Astral mass spectrometry to analyse the immunopeptidome of matched tumour tissue and plasma samples from five melanoma patients collected at the time of tumour resection. We identified 6,590-17,690 non-redundant HLA-I peptides from tumour tissue (5-25 mg input) and 5,213-10,089 non-redundant HLA peptides from plasma-derived sHLA complexes (200-571 μL input within the volume of a routine biobank aliquot). Plasma-derived sHLA ligandomes retained key features of membrane-bound tumour HLA-I presentation, including dominant 9-mer peptide length distributions and conserved HLA-binding characteristics. Peptide recovery was strongly concordant between compartments following normalisation (Pearson r = 0.92), indicating that ligandome depth and recovery were primarily driven by intrinsic biological variation rather than sample input. Tumour-associated antigens were consistently detected in circulating sHLA peptides. Cryptic peptides derived from "peptideins" were preserved in circulation and comprised approximately 1% of the total repertoire. Somatic patient-specific variant calling revealed a candidate neo-peptide is also preserved and presented in sHLA. To assess tumour specificity and biomarker potential, identified HLA peptides were mapped to their corresponding source proteins and compared against healthy sHLA and benign tissue reference datasets. This analysis identified 247 candidate melanoma-associated source proteins not detected in healthy plasma or benign tissue reference datasets. Among these, 9 source proteins were recurrently detected across at least 4 of 5 patients, representing priority candidates for further biomarker validation. In this proof-of-concept study of five matched patients, these findings indicate that circulating sHLA ligandomes preserve core features of tumour antigen presentation and provide proof-of-concept support for plasma immunopeptidomics as a minimally invasive approach for antigen discovery and biomarker hypothesis generation. Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.”

Key takeaway: The circulating sHLA peptides in plasma mirror what’s actually happening on the tumor surface. Researchers used advanced mass spectrometry and found thousands of unique HLA-bound peptides per patient. The overlap between tumor and plasma samples was strong—over 90% correlation after adjusting for input size. That means what’s circulating in the blood is a reliable snapshot of what the tumor is showing to the immune system.

Here’s why this matters for peptide researchers:

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Plasma-derived sHLA complexes retained the key features of tumor HLA presentation, including the “classic” 9-mer peptide length and correct HLA binding.

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Tumor-associated and cryptic peptides, including rare neoantigens, showed up in the blood. About 1% of the detected peptides were cryptic, derived from unusual protein sources (“peptideins”).

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They mapped 247 candidate melanoma-associated source proteins that don’t show up in healthy controls, with 9 showing up across almost every patient.

This means researchers can now hunt for new biomarkers, immune targets, and peptide signatures for melanoma—and possibly other cancers—without needing invasive tissue samples. For anyone exploring the potential of the human immunopeptidome, this is a proof-of-concept that the sHLA plasma approach works. Check out the latest in peptide research or find new workflow ideas for your own lab.

Bottom line: Blood-based peptide discovery just got a shot of credibility. The field is wide open for bigger studies and smarter biomarker hunting.

Back to News Read original on Mol Cell Proteomics

The soluble HLA repertoire captures neoantigenic, cryptic, and tumour-associated peptides in melanoma.

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