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

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Loss-of-function mutations in Janus kinase 1/2 (JAK1/2) impair tumor immunogenicity by reducing interferon regulatory factor 1 (IRF1) induction, leading to poor response to cancer immunotherapy.
• Developing novel reagents that enhance IRF1 expression independent of JAK activity is crucial for improving cancer immunotherapy outcomes.

Purpose of the Study:

• To investigate the potential of proteasome inhibitors in increasing IRF1 expression independent of JAK activity.
• To evaluate the effect of proteasome inhibitors on IRF1 downstream molecules and their impact on cancer immunogenicity.

Main Methods:

• Utilized various cancer types, including melanoma.
• Employed genetic and chemical inhibition of JAK signaling pathways.
• Assessed IRF1 expression and its downstream targets, including programmed death-ligand 1 (PD-L1), PD-L2, and human leukocyte antigen class I molecules.

Main Results:

• Proteasome inhibitors activated IRF1 downstream pathways in a JAK-independent manner across diverse cancer types.
• Proteasome inhibitors increased IRF1 expression by inhibiting its degradation in melanoma cells.
• The expression of PD-L1, PD-L2, and human leukocyte antigen class I molecules was induced by proteasome inhibitors.
• IRF1 induction by proteasome inhibitors was confirmed to be independent of JAK activity.

Conclusions:

• Proteasome inhibitors can enhance cancer immunogenicity by upregulating IRF1 expression through a JAK-independent mechanism.
• These findings suggest that proteasome inhibitors could serve as effective adjuvants to potentiate cancer immunotherapy efficacy.