Proteomic profiling of a patient with cutaneous melanoma metastasis regression following topical contact sensitizer diphencyprone and immune checkpoint inhibitor treatment

Abstract

Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of advanced melanoma, but many patients do not respond to ICIs alone, and thus there is need for additional treatment options. Topical immunomodulators such as diphencyprone (DPCP) also have clinical use in advanced melanoma, particularly in the treatment of cutaneous metastases. In a previous report, we characterized the enhanced clinical response to dual agent immunotherapy with pembrolizumab and DPCP in a patient with cutaneous melanoma metastases. To improve mechanistic understanding of this response, we analyzed proteomic data using the Olink immuno-oncology panel of 96 biomarkers from tissue and serum samples of this patient throughout his treatment course. Particular attention was paid to programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) given they are all targeted by ICIs in clinical practice. These proteins were upregulated during the period of DPCP monotherapy, then downregulated during pembrolizumab monotherapy, and then robustly upregulated again during dual therapy. Although not exclusively, the induction of checkpoint inhibitor proteins in the presence of DPCP suggests potential synergy between this agent and ICIs in the treatment of cutaneous melanoma metastases. Large-scale investigation is warranted to further evaluate this potential novel combination therapeutic approach.

Case report: Regression of in-transit metastases of cutaneous squamous cell carcinoma with combination pembrolizumab and topical diphencyprone

“…DPCP has been shown to increase both PD-1 gene expression in tissue and PD-1 protein levels in the serum (9). By increasing the PD-1 targets, DPCP may amplify the inhibition induced by pembrolizumab (9), thus allowing for synergistic anti-tumor immune activation.…”

“…DPCP has been shown to increase both PD-1 gene expression in tissue and PD-1 protein levels in the serum (9). By increasing the PD-1 targets, DPCP may amplify the inhibition induced by pembrolizumab (9), thus allowing for synergistic anti-tumor immune activation. Clinically and histopathologically, the patient's DPCP-treated metastases demonstrated earlier regression in comparison to those treated with ICI alone.…”

Bottom-Up Proteomics: Advancements in Sample Preparation

“…Proteomics is an analytical technique that examines protein expression, structures, functions, and interactions in a particular cell, tissue, body fluid, or organism [ 1 , 2 ]. Protein composition and abundance are currently analyzed to identify disease markers or treatment mechanisms, as all changes in proteomes indicate pathological or biological processes [ 3 , 4 , 5 ]. Over the last two decades, liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based proteomics has been developed as an alternative to time-consuming and labor-intensive gel-based proteomics and immunoassays [ 6 ].…”