Enhancer RNA-based modeling of adverse events and objective responses of cancer immunotherapy reveals associated key enhancers and target genes

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 or CTLA-4 are emerging and effective immunotherapy strategies. However, ICI-treated patients present heterogeneous responses and adverse events, thus demanding effective ways to assess benefit over risk before treatment. Here, by integrating pan-cancer clinical and molecular data, we tried to predict immune-related adverse events (irAEs, risk) and objective response rates (ORRs, benefit) based on enhancer RNAs (eRNAs) expression among patients receiving anti-PD-1/PD-L1 therapies. We built two tri-variate (eRNAs) regression models, one (with ENSR00000326714, ENSR00000148786, and ENSR00000005553) explaining 71% variance (R=0.84) of irAEs and the other (with ENSR00000164478, ENSR00000035913, and ENSR00000167231) explaining 79% (R=0.89) of ORRs. Interestingly, target genes of irAE-related enhancers, including upstream regulators of MYC, were involved in metabolism, inflammation, and immune activation, while ORR-related enhancers target PAK2 and DLG1 which participate in T cell activation. More importantly, we found that ENSR00000148786 probably enhanced TMEM43/LUMA expression mainly in B cells to induce irAEs in ICI-treated patients. Our study provides references for the identification of immunotherapy-related biomarkers and potential therapeutic targets during immunotherapy.