Proteasome Inhibition Induces IRF1 Downstream Molecules Independently of JAK Activity in Cancers

抄録

Loss-of-function mutations in Janus kinase 1/2 (JAK1/2) cause low tumor immunogenicity through defects in the induction of the transcription factor interferon regulatory factor 1 (IRF1), resulting in non-responsiveness to cancer immunotherapy reagents. Therefore, the discovery of reagents that increase IRF1 expression independent of JAK activity is clinically important for the success of cancer immunotherapy reagents. We herein demonstrated that proteasome inhibitors activated IRF1 downstream pathways in a JAK-independent manner in various cancer types. Proteasome inhibitors increased IRF1 expression by inhibiting the degradation of IRF1 in melanoma. Furthermore, proteasome inhibitors induced the expression of the IRF1 downstream molecules, programmed death-ligand 1 (PD-L1), PD-L2, and human leukocyte antigen class I molecules. The induction of IRF1 expression by proteasome inhibitors was also detected in cancer types other than melanoma. Moreover, we showed that the induction of IRF1 expression was independent of JAK activity by genetic or chemical inhibition of JAK. Therefore, proteasome inhibitors may serve as adjuvants that potentiate the efficacy of cancer immunotherapy reagents by enhancing cancer immunogenicity.