Abstract 1083: T cell receptor-associated genes as biomarkers of survival in anti-PD-1 treated cancer patients
Authors: Szonja Anna Kovacs, Balazs Gyorffy
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint inhibitors (ICIs) aim to restore T-cell function in the tumor microenvironment, but predicting patient response remains challenging. T-cell abundance and T-cell receptor (TCR) signaling are critical for the effectiveness of ICI therapies. While PD-L1 expression is a commonly used biomarker, its predictive accuracy is inconsistent. Exploring alternative biomarkers could improve response prediction and patient outcomes. Methods: We integrated multiple gene expression cohorts from cancer patients treated with immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-CTLA-4). Corresponding clinical annotation data were incorporated for survival and biomarker studies. Survival analysis was performed using Cox regression, and Gene Ontology (GO) enrichment analysis was conducted on both pre-treatment (samples taken before ICI therapy) and on-treatment (samples collected during or after therapy) groups. Published survival data were excluded if no progression or death occurred, and follow-up ended within 12 months. Results: The complete database includes 1,297 patients with relapse-free survival data and 1,554 patients with overall survival (OS) data. Patients with higher expression of genes associated with the CD4+ or CD8+ T-cell lineage commitment pathway (GO:0043369) demonstrated improved OS. Notably, elevated expression of T-cell receptor beta constant 2 (TRBC2; HR=0.38, log-rank P=1E-03, FDR=5%), Cluster of Differentiation 247 (CD247; HR=0.37, log-rank P=1.7E-03, FDR=5%), and Cluster of Differentiation 3E (CD3E; HR=0.35, log-rank P=1.4E-03, FDR=5%) correlated with better OS after anti-PD-1 therapy. To determine whether these findings reflect a pre-existing immune-infiltrated tumor microenvironment or an immune system boost induced by anti-PD-1 therapy, we also analyzed pre-treatment samples. Higher expression of TRBC2 (HR=0.49, log-rank P=4.4E-05, FDR=1%), CD247 (HR=0.49, log-rank P=4.9E-07, FDR=1%), and CD3E (HR=0.42, log-rank P=9.5E-07, FDR=1%) in pre-treatment samples were also associated with better survival. PD-L1 (CD274) expression is a commonly used but controversial biomarker for ICI therapy. Patients with high PD-L1 expression before anti-PD-1 treatment showed better relapse-free survival (HR=0.61, log-rank P=4.1E-10, FDR=1%) and overall survival (HR=0.61, log-rank P=5.6E-04, FDR=5%). These results demonstrate that, as expected, an already immunologically "hot" tumor predicts a better response and, consequently, improved survival with anti-PD-1 immunotherapy. The complete ICI cohort was integrated into our established web platform (www.kmplot.com) to enable independent future biomarker discovery. Conclusions: T-cell receptor complex-associated genes, such as TRBC2, CD247, and CD3E, are robust predictors of survival both before and after anti-PD-1 therapy. Citation Format: Szonja Anna Kovacs, Balazs Gyorffy. T cell receptor-associated genes as biomarkers of survival in anti-PD-1 treated cancer patients. [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 1083.