Abstract B040: Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response

Abstract Immune-checkpoint 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. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors of 5 cancer types 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. Our analysis revealed a lack of cancer-cell intrinsic gene expression signatures associated with ICB response across tumor types. Strikingly, PD-L1 expression in stromal cells, but not cancer cells, is correlated with ICB response across cancer types. In stromal cells, we identified multiple immunomodulators and checkpoint genes associated with ICB response across cohorts and tumor types. Many of these genes, such as CXCL9, CXCL13, and IFNG, have previously been linked with ICB response. In addition, we uncovered a subset of novel and potentially immune-suppressive genes, including FCER1A, that negatively correlated with response. Using these conserved stromal-specific gene signatures, we developed a multivariate classifier of ICB response that demonstrated improved accuracy over existing biomarkers in unseen patient cohorts and tumor types, including a cohort of 50 newly sequenced late stage lung cancer patients treated with ICB. In summary, our unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic expression signatures of ICB response conserved across tumor types, suggesting that cancer cells lack tissue-agnostic transcriptomic features of ICB response. Our results challenge the prevailing dogma that cancer cells present tissue-agnostic molecular markers that modulate immune activity and ICB response, which has implications on the development of improved ICB diagnostics and treatments. Citation Format: Yu Amanda Guo, Aaron Tan, Tanmay Kulshrestha, Mei Mei Chang, Dawn Lau, Lan Ying Wang, Timothy Tay, Irfahan Kassam, Egor Revkov, Simone Rizzetto, Iain Tan, Daniel Tan, Anders Skanderup. Transcriptomic meta-analysis identifies robust, tissue-agnostic gene expression signature of immune checkpoint blockade response [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B040.