Abstract 4622: Proteomic insights into anti-CTLA4 therapy resistance in metastatic melanoma: Pathway-specific biomarkers for treatment response

Abstract The current standard of care for metastatic melanoma includes immune checkpoint inhibitor (ICI) therapy that, although revolutionary for melanoma treatment, is ineffective for most patients long-term. According to clinical data, patients have a limited response to anti-PD1 and anti-CTLA4 immunotherapy treatment, with overall response rates of roughly 40% and 15% respectively, and increasing to 60% with combination therapy. However, with half of patients not responding to combination therapy or acquiring resistance to therapy as the treatment progresses, there is an evident need for identifying and vetting more reliable biomarkers for treatment response or resistance. Although up-to-date ICI treatment often includes both anti-PD1 and anti-CTLA4 effectiveness, the different treatment regimens have independent factors of patient responsiveness. Anti-PD1 therapy directly mediates tumor-immune interactions, permitting immune system activation; however, protein levels of PD1 or its ligand is a poor indicator of responsiveness. Recent data suggests an enrichment in oxidative phosphorylation and lipid metabolism in anti-PD1-responsive patients. Identifying key biomarkers for response to CTLA4 therapies is more nuanced, as its mode of action occurs outside of the tumor microenvironment. Due to this, the approach to identifying tumoral patterns or biomarkers that indicate anti-CTLA4 responsiveness is more nuanced. To identify anti-CTLA4 response-specific biomarkers, we collected metastatic melanoma tumors from patients prior to ICI treatments and sorted them as responders or non-responders depending on patient response. The tumor proteome from patients treated with anti-CTLA4 therapy was analyzed via tandem mass tag (TMT) mass spectrometry to mark differentially expressed proteins between responder and non-responder groups. Comparative pathway analyses on platforms such as Ingenuity Pathway Analysis (IPA) and GSEA found several distinct protein and pathway enrichments, including that anti-CTLA4 non-responding patient tumors were enriched for pathways such as oxidative phosphorylation and fatty acid metabolism. This anti-CTLA4-specific enrichment is distinct from anti-PD1-treated patient tumors. These differences between the ICI treatment responses could be used clinically to inform patient treatment plans and improve the likelihood for response to initial treatments. Future studies will elucidate the function of specific proteins and pathways in ICI resistance as well as identify potential novel neoadjuvant therapies to increase patient responsiveness to ICI therapies. Citation Format: Katherine Bronson, Nathan Avaritt, Erin Taylor, Alan Tackett. Proteomic insights into anti-CTLA4 therapy resistance in metastatic melanoma: Pathway-specific biomarkers for treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4622.