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Proteomic profiling of advanced melanoma to predict therapeutic response to anti-PD-1 therapy

ABSTRACT: Despite high clinical need, hardly any biomarker can accurately predict if patients with metastatic melanoma will respond to anti-PD-1 therapy. In this multicenter study we applied depletion and enrichment methods prior to different proteomic techniques to analyze the discovery cohort (n=56) and discovered several significantly regulated proteins as well as commonly enriched processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. We then analyzed two independent serum cohorts (n=96; n=17) confirming significant differences between R and NR. In addition, literature-based validation revealed 30 markers overlapping with previously published signatures, and survival analysis revealed that overexpression of 17 markers correlated with lower overall survival in melanoma patients. Primary melanoma tumor cells from NR also exhibit a distinctive immunophenotype characterized by CD29, CD49e, CD91, CD105, CD151, CD157, CD248 and CD280, and the TME could represent a potential target for therapy. Ultimately, this led to a potential marker signature with 8 key markers identified in at least two independent serum cohorts: CFHR3, CRP, LRG1, LYVE1, MMRN1, S100A8, SAA2, and TIMP1.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

DISEASE(S): Melanoma

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD039469 | Pride | 2023-08-18

REPOSITORIES: Pride

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	22-Prot-1366_RA1_1_10865.d.rar	Other
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	22-Prot-1368_RA3_1_10867.d.rar	Other
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Proteomic profiling to predict therapeutic response to anti-PD1 therapy in advanced melanoma

Project description:Purpose Antibody-blockade of PD-1 shows durable responses, but so far, few biomarkers accurately predict if patients with metastatic melanoma will respond. Experimental design We analyzed baseline serum samples (n=56) and tumor cell cultures (n=8), from melanoma patients treated with anti-PD1 therapy. Two approaches concentrating low abundant proteins in serum and two different mass spectrometry (MS) methods were applied: depletion of high abundant proteins with shotgun-MS, and N-glycosite enrichment combined with SWATH-MS. Tumor cell cultures were processed as whole cell lysates with subsequent shotgun-MS. Results Focusing on the non-responder proteome, we identified pathways such as inflammatory processes, cell adhesion and migration, scavenger receptor activity, RAGE receptor binding, platelet aggregation, neutrophil degranulation and integrin signaling to be upregulated. Analyzing the tumor cell proteome revealed a distinctive immunophenotype with CD antigens highly overexpressed in non-responders. Validation of a subset of these markers, performed by immunofluorescence staining of a tissue microarray, revealed a higher mean of positive cells in the tumor microenvironment of non-responders. Validation of serum proteome markers on a second baseline cohort by using a timsTOF for ion mobility MS, revealed significant differences between responder and non-responder for the proteins ORM2, SERPINA1, EFEMP1, and VASN. TCGA survival analysis demonstrated prognostic significance for multiple proteins of our signature correlating with lower overall survival in melanoma patients. Based on this study, we suggest a protein-panel for responsiveness to PD-1 blockade consisting of 14 serum and 33 tumor cell markers that will be the basis for further research.

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