Inhibition of Aspartate β-Hydroxylase Enhances Anti-Tumor Immunity

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Aspartate β-hydroxylase (ASPH) promotes cancer progression and suppresses natural killer (NK) cell activity.
• ASPH inhibition has demonstrated anti-metastatic effects in preclinical models.
• Understanding ASPH's role in modulating anti-tumor immunity is crucial for developing novel cancer therapies.

Purpose of the Study:

• To investigate the impact of ASPH inhibition on inducing anti-tumor immunity.
• To identify the specific immune cells involved in the anti-tumor response following ASPH inhibition.
• To evaluate the efficacy of combined ASPH inhibition and immune stimulation against tumors.

Main Methods:

• Utilized a mouse TC-1/A9 model with reversible downregulation of major histocompatibility class I (MHC-I) molecules.
• Combined ASPH inhibition with innate (ODN1826) or adaptive (DNA vaccination) immune stimulation.
• Assessed anti-tumor response via tumor growth, immune cell depletion, ELISPOT assays, flow cytometry, and single-cell RNA sequencing (scRNA-seq).

Main Results:

• ASPH inhibition alone did not reduce tumor growth but significantly enhanced tumor reduction when combined with DNA vaccination.
• CD8+ T cells were critical for the anti-tumor immunity induced by combined ASPH inhibition and DNA vaccination.
• Combined therapy increased CD8+ T cell response, decreased regulatory T cells in tumors, and activated NK cells, macrophages, and dendritic cells.

Conclusions:

• ASPH inhibition potentiates T-cell-mediated adaptive immunity, particularly when combined with DNA vaccination.
• The combined approach is effective against tumors with MHC-I downregulation, which are often resistant to T-cell therapies.
• ASPH inhibition holds potential for improving immunotherapies across diverse tumor MHC-I expression levels.