Abstract 287: Circulating metabolites associated with response to immune checkpoint blockade in melanoma

Abstract Introduction: Metabolism plays a crucial role in tumor microenvironment dynamics and may influence response to immune checkpoint blockade (ICB). We examined the relationship between the serum metabolomic and lipidomic profiles and outcomes with ICBs in melanoma. Methods: Patients with melanoma initiating standard of care anti-PD1-based ICB therapy with neoadjuvant or palliative intent were prospectively enrolled. Clinical characteristics were abstracted and survival and objective response using RECIST 1.1 were assessed. Patients with complete or partial response were classified as the response (R), and the remainder as the non-response (NR) cohort. Baseline serum metabolome profiling was conducted at the University of Texas MD Anderson metabolomics core using high-resolution mass spectrometry to assess global lipids and semi-targeted metabolites using in-house standard metabolite library and compared between R and NR. Results: A total of 67 patients (median age 61 years, 70% male) were included. The majority (67%) received ICB for stage IV disease while 34% were treated in the neoadjuvant setting. The most common ICB regimen was anti-PD-1 and anti-CTLA4 combination (55.2%), followed by anti-PD-1 and anti-LAG3 combination (35.8%). Overall objective response rate was 52.5%. A total of 1, 161 lipid metabolites and 120 semi-targeted metabolites were identified and analyzed. Global metabolite profiles of the R and NR cohorts suggested up-regulation of pentose phosphate pathway metabolites and downstream nucleotide precursors in the R cohort. Global lipidome profile demonstrated similarities between groups, although a degree of clustering effect by response status was observed in principal component analysis (data will be presented). In the R cohort, differentially overrepresented lipid classes included plasma membrane lipids (p<0.001, false detection rate [FDR] q-value=0.004) and inflammation-associated lipids such as sphingolipids (p<0.005, q=0.006), diacylceramides (p=0.001, q=0.008), diradylglycerols (p=0.003, q=0.016), diacylglycerols (p<0.001 q=0.004), and sphingosine-containing lipids (p=0.003, q=0.017). Additionally, polyunsaturated fatty acid (PUFA)-containing lipids in general were down-regulated (p<0.001, q<0.001), with notable down-regulation of PUFA-enriched triacylglycerides (TAGs) such as TAG 52:7, TAG 50:5, TAG 54:7, TAG 56:9, TAG 50:4, TAG 54:8 (p<0.005, q<0.05). Conclusion: Distinct lipid class differences were observed between R and NR to ICB in melanoma. Together, these observations prompt the hypothesis that melanomas that are highly responsive to immunotherapy may efflux metabolites representing up-regulated nucleotide synthesis and dysregulated lipid metabolism representing a highly inflammatory state and potentially up-regulated autophagy. Citation Format: Nazli Dizman, Iqbal Mahmud, Julie Simon, Elizabeth Sirmans, Hussein A. Tawbi, Jeffrey Gershenwald, Michael Davies, Nadim Ajami, Carrie Daniel-MacDougall, Jennifer Wargo, Philip Lorenzi, Jennifer McQuade. Circulating metabolites associated with response to immune checkpoint blockade in melanoma [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 287.