Abstract 3227: Components of interleukin-4 signaling are enriched in melanoma patients who respond to anti-PD-1 or anti-CTLA-4 therapy

Abstract Background: Immune checkpoint inhibitors represent an advanced class of immunotherapy drugs used to treat various cancers, including melanoma, particularly in advanced stages. These therapies work by targeting immune checkpoints — proteins such as PD-1, PD-L1, and CTLA-4 — that act as brakes on the immune system. Prognostic biomarkers are essential for predicting disease outcomes, thereby enabling improved patient management. Methods: We obtained transcriptomic and clinical data from melanoma patients treated with immune checkpoint inhibitors through the NCBI Gene Expression Omnibus and CRI iAtlas. After reviewing 246 datasets, we excluded those involving cell lines, unrelated diseases, or treatments. The expression data were quantile-normalized, and statistical analyses were conducted using the R environment. Survival data were excluded for patients without an event if follow-up ended before 12 months. Cox regression was applied to overall survival (OS) data. Results: Altogether, 423 melanoma samples had sufficient data for survival analysis. Elevated expression of IL4R (interleukin-4 receptor, HR=0.33, FDR=2%, log-rank P=5.7E-04), JAK1 (Janus kinase 1, HR=0.3, FDR=1%, log-rank P=2.8E-04), GFI1 (growth factor independence 1, HR=0.35, FDR=5%, log-rank P=2.2E-03), and PTPN6 (protein tyrosine phosphatase non-receptor type 6, also known as SHP-1, HR=0.31, FDR=5%, log-rank P=1.9E-03) correlated with improved OS after anti-PD-1 therapy. Similar findings were observed after anti-CTLA-4 therapy for IL4R (HR=0.13, FDR=1%, log-rank P=3.2E-04), JAK1 (HR=0.14, FDR=1%, log-rank P=9.3E-04), and PTPN6 (HR=0.09, FDR=1%, log-rank P=2E-04). Signals mediated by interleukin-4 and interleukin-13 through these genes promote improved immune responses, cell survival, and differentiation. Finally, the Kaplan-Meier Plotter (www.kmplot.com) web platform was updated with our newly compiled immunotherapy cohort. Conclusions: In melanoma patients, elevated expression of IL4R, JAK1, GFI1, and PTPN6 following anti-PD-1 and anti-CTLA-4 immunotherapies may enhance immune cell recognition, increase treatment efficacy, and extend survival. Our analytical platform supports a deeper understanding of patient responses and facilitates biomarker validation in a large cohort of melanoma patients. Citation Format: Szonja Anna Kovacs, Janos Tibor Fekete, Balazs Gyorffy. Components of interleukin-4 signaling are enriched in melanoma patients who respond to anti-PD-1 or anti-CTLA-4 therapy [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 3227.