Dual function of DOT1L suppresses tumor intrinsic immunogenicity in Hepatocellular carcinoma [RNA-seq]

Checkpoint inhibitor therapy for Hepatocellular carcinoma (HCC) remains limited in patients’ overall response rate. Discovery and development of more effective combinatorial approaches in HCC checkpoint immunotherapy is urgent. Here, through CPlSPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress anti-tumor immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type-I interferon response, and meanwhile lowers ZEB1 levels to further unleash the expression of interferon simulated genes. In turn, we demonstrate that DOT1L loss or treatment with the selective DOT1L inhibitor EPZ-5676 sensitizes tumors to immune checkpoint blockade by increased immune infiltration in mouse. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mouse model. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.