A transcriptome-wide meta-analysis reveals lack of cancer-cell intrinsic determinants of response to immune checkpoint blockade

Immune-checkpoint therapy (ICT) has conferred significant and durable clinical benefit to some cancer patients. However, most patients do not respond to ICT, and reliable biomarkers of ICT response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICT-treated patients and tumors with expected ICT outcomes based on microsatellite status. Using a transcriptome deconvolution approach, we inferred cancer and stroma-specific gene expression differences and identified cell-type specific features of ICT response across cancer types. Consistent with current knowledge, stromal expression of CXCL9, CXCL13, IFNG, and CD274 were among the top positive determinants of ICT response. Interestingly, we also identified a group of potential immune-suppressive genes, including FCER1A , associated with poor response to ICT. Surprisingly, the unbiased transcriptome-wide analysis failed to identify cancer-cell intrinsic features of ICT response conserved across tumor types. Overall, our results suggest that cancer cells lack tissue-agnostic molecular determinants of ICT response, which has implications for the development of improved ICT diagnostics and treatments. ### Competing Interest Statement The authors have declared no competing interest.