Abstract 6393: The predictive role of TNF-related genes in patients receiving immune checkpoint inhibitors
Authors: Obada Ehab Ababneh, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary Nesline, Sarabjot Pabla, Jeffrey Conroy, Paul DePietro, Heidi Ko, Razelle Kurzrock
Journal: Cancer Research (2024)

Abstract Introduction: Not all patients respond to immune checkpoint inhibitors (ICI) even when they have favorable FDA-approved biomarkers. The tumor necrosis factor superfamily (TNFSF) and tumor necrosis factor receptor superfamily (TNFRSR) play critical roles in various biological processes, including inflammation, immune regulation, and cell death. In this study, we sought to investigate the predictive role of TNF-related genes in patients receiving ICI. Methods: The RNA expression levels of 18 TNF-related genes were assessed in a pan-cancer cohort of 217 patients treated with immune checkpoint inhibitors (ICI) at the University of California San Diego (UCSD) Moores Cancer Center. Using a reference population of 735 tumors and 35 histologies, transcript abundance was adjusted to internal housekeeping gene profiles and rated (0-100th percentile). The patients were clustered into two groups based on the 18 TNF-related genes expression using Ward’s hierarchical clustering. Associations between overall survival and previously demonstrated independent ICI predictive variables were assessed. Bonferroni correction for multiple comparisons was used and considered statistically significant when p-value ≤ 0.05. Results: Four TNF-related genes (CD137, CD70, GITR, and TNFSF9) were associated with positive programmed death-ligand 1 (PD-L1) expression (PD-L1≥1% immunohistochemistry TPS), while TNFSF18 was associated with negative PD-L1 expression (corrected p-value&amp;lt;0.05). No gene was associated with microsatellite instability-high (MSI-H) or high tumor mutational burden (TMB-H) (TMB≥10 mutations/Mb) (corrected p-value&amp;gt;0.05). We clustered the patients based on their 18 TNF-related genes expression into two signature clusters, high (n=94) and low (n=123). Patients in the high expression signature cluster were more likely to have high PD-L1 compared to the low expression cluster (corrected p-value&amp;lt;0.05). The high expression signature cluster was associated with better survival compared with the low expression cluster (HR=1.49, 95%CI: 1.05-2.13 (p=0.026)). When adjusting for TMB, MSI, PD-L1, TP53 and KRAS status, the TNF high expression signature cluster was still associated with better overall survival (HR=1.71, 95%CI:1.11-2.66 (p=0.016)). Other than the TNF high expression signature cluster group, only the presence of KRAS mutation was a predictor of a longer survival (HR=2.09, 95%CI:1.28-3.42 (p=0.003)). Conclusion: A high TNF-related gene expression profile may serve as an independent predictor for longer overall survival for patients treated with ICI. Citation Format: Obada Ehab Ababneh, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary Nesline, Sarabjot Pabla, Jeffrey Conroy, Paul DePietro, Heidi Ko, Razelle Kurzrock. The predictive role of TNF-related genes in patients receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6393.