Combining anti-PD1 and vorinostat improves anti-tumor treatment in IDH-mutant brain tumors

Enhancer RNA (eRNA) is critical element with highly specific pattern in regulatory network across infiltrated immune cells. Herein we developed eRNA immunotherapy signature (eRIS) based on these eRNAs which significantly connected with anti-tumor immune cells. The eRIS was highly correlated with objective response rate (ORR) to immune checkpoint blockade (ICB) treatment, and was significantly increased in these patients who benefit from ICB treatment. By integrating with pharmacogenomics datasets, we screened hundreds of eRIS associated anti-cancer drugs, which showed potential in improving immunotherapy with cancer type or subtype-specific specific manner. We further characterized one drug, the HDAC inhibitor vorinostat, in isocitrate dehydrogenase mutant gliomas, and found Combining vorinostat with anti-PD-1 could decrease tumor size and increase survival time in vivo by enhancing abundance of anti-tumor immune cells. We further provided eRIS markers which showed strong capacity of eRIS in predicting immunotherapy response in clinical samples or animal models. Our study revealed the potential utility of eRIS to improve immunotherapy response by identifying combinational drugs, that provide novel insights to benefit patients in certain cancer or subtypes. Overall design: To investigate the efficiency of combining anti-PD1 and vorinostat, we established the LGG IDH-mutant tumor model in mouse by stereotactic injection with the 1:1 mixture of DF-1 cells expressing R132H-mutant IDH and DF-1 cells expressing PDGFB into nesin-TVA mice.