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.