Abstract B048: Proteomic approaches for the identification of druggable protein and epigenetic targets to complement melanoma immunotherapy

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) have shown encouraging success for treatment of melanoma; however, approximately half of patients with advanced melanoma have primary ICI resistance and sub-populations of initially responding patients develop secondary resistance. To help address this, our group has used quantitative proteomic workflows to identify druggable molecular pathways in these non-responders. Specifically, we are targeting the identification of protein pathways involved in regulation of gene transcription and chromatin modification as these are upstream events in cellular programming. Experimental Procedures: We have used cutting-edge proteomic workflows to identify proteins and histone post-translational modifications that are dysregulated in ICI nonresponsive patient melanoma. Proteins were isolated from FFPE patient melanomas and analyzed by high-resolution mass spectrometry with a Thermo Fusion Orbitrap mass spectrometer. Mass spectrometric data was searched for proteins and histone post-translational modifications dysregulated in ICI nonresponding melanomas. Pathway analysis provided for the identification of molecular pathways dysregulated in ICI nonresponders. New Data: We have published a smaller-scale version of this proteomic study comparing 4 responding and 4 nonresponding melanomas (Sci Reports 2017;7:807). In new data, we have increased the sample size of this comparison to provide increased power and significance. We have also expanding our quantitative proteomic analysis by incorporating the use of Thermo Tandem Mass Tagging with FFPE samples. Furthermore, we present new workflows using fresh melanoma tumors that provide for specific enrichment of melanoma cells from human tumors. Conclusions: We have identified protein and histone epigenetic pathways that are dysregulated in ICI nonresponsive patient melanomas. These molecular pathways could be prime targets for therapeutic development for increasing responsiveness to ICI therapy. Furthermore, we have extended our proteomic capabilities to the analysis of enriched populations of melanoma cells isolated from fresh human tumors, which will provide for cell type-specific proteomic studies. Citation Format: Alan Tackett. Proteomic approaches for the identification of druggable protein and epigenetic targets to complement melanoma immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B048.