Abstract P57: A Transcriptome-Wide Meta-Analysis Reveals Lack Of Cancer-Cell Intrinsic Determinants Of Response To Immune Checkpoint Blockade

Abstract Immune-checkpoint blockade therapy (ICB) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Current FDA-approved biomarkers for ICB include PD-L1 expression, microsatellite instability (MSI), and high tumor mutation burden (TMB) of 10mutations/Mb. In addition, gene expression signatures of tumor immune phenotypes have been proposed to predict for ICB response. Despite these efforts, there is a lack of large-scale transcriptome-wide studies to identify and characterize potential biomarkers of ICB response conserved across cancer types in a cell type specific manner. Here, we performed a transcriptome-wide meta-analysis across 1, 486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status. Using a robust transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICB response across cancer types. We identified 59 stroma-specific differentially expressed genes associated with ICB-response, which were strongly enriched in immune-related pathways and processes. Stromal expression of CXCL9, CXCL13, IFNG, and CD274 were among the top positive determinants of ICB response, consistent with current knowledge. Interestingly, we also identified a group of potential immune-suppressive genes, including FCER1A, associated with poor response to ICB. Surprisingly, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic features of ICB response conserved across tumor types. Overall, our results suggest that cancer cells lack tissue-agnostic molecular determinants of ICB response, which has implications for the development of improved ICB diagnostics and treatments. Citation Format: Yu Amanda Guo, Tanmay Kulshrestha, Mei Mei Chang, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Aaron C. Tan, Daniel S. W. Tan, Iain Beehuat Tan, Anders Jacobsen Skanderup. A Transcriptome-Wide Meta-Analysis Reveals Lack Of Cancer-Cell Intrinsic Determinants Of Response To Immune Checkpoint Blockade abstract. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84 (8Suppl): Abstract nr P57.