HVJ-E links Apolipoprotein d to antitumor effects.

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Virotherapy utilizes viruses to kill cancer cells and stimulate immune responses.
• The precise mechanisms of non-replicating virotherapy, such as UV-irradiated Hemagglutinating Virus of Japan envelope (HVJ-E), remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mediators of anti-tumor effects induced by UV-irradiated HVJ-E.
• To investigate the role of Apolipoprotein d (Apod) in mediating HVJ-E's anti-tumor activity.

Main Methods:

• RNA sequencing, gene knockout, and drug-inducible gene expression systems were employed to identify key genes.
• Genome-wide CRISPR library screening, in situ biotinylation, mass spectrometry, flow cytometry, and mouse models were used to analyze Apod's function.
• Investigated the interaction of Apod with ERK2 and its impact on nuclear translocation and NKG2D-ligand expression.

Main Results:

• UV-irradiated HVJ-E exerts anti-tumor effects through Interferon regulatory factor 7 (Irf7)-induced Apod expression in tumor cells.
• Apod significantly suppresses tumor growth, even in tumors resistant to HVJ-E, by increasing NKG2D-ligand genes.
• Apod associates with ERK2, inhibiting its nuclear translocation and Importin7, thereby upregulating NKG2D-ligands and reducing tumor growth.
• Combination therapy with Apod and anti-OX40 antibody demonstrated potent anti-tumor activity and T cell activation.

Conclusions:

• The study reveals the molecular pathway through which HVJ-E mediates anti-tumor effects, involving Irf7 and Apod.
• These findings offer insights into developing novel therapeutic strategies to enhance anti-tumor immunity.