DNA Ligase 4 Inhibition Sensitizes Prostate Cancer to Immune Checkpoint Blockade In Vivo

Area of Science:

• Oncology
• Cancer Biology
• Immunotherapy

Background:

• Prostate cancer is a prevalent malignancy with poor prognosis linked to DNA ligase IV (LIG4) expression.
• Current anti-PD-1 immunotherapy shows limited efficacy in prostate cancer due to low PD-L1 and T cell infiltration.
• A novel genetically engineered in vivo model was developed to study LIG4 inhibition's effects.

Purpose of the Study:

• To investigate the impact of DNA ligase IV (LIG4) inhibition on prostate tumorigenesis.
• To assess the potential of LIG4 inhibition to overcome resistance to anti-PD-1 immunotherapy.

Main Methods:

• Utilized a genetically engineered mouse model (Lig4+/+;TAg and Lig4+/-;TAg) for prostate cancer.
• Administered anti-PD-1 antibody or IgG to tumor-bearing mice.
• Quantified gene and protein expression (LIG4, PD-L1), DNA damage, senescence, cell death markers, and cancer stem cell populations.

Main Results:

• LIG4 inhibition induced DNA double-strand breaks, cellular senescence, and reduced prostate intraepithelial neoplasia and tumorigenesis.
• Inhibition of LIG4 decreased prostate cancer stem cell fraction and proliferation.
• Resistant prostate cancers showed increased PD-L1 expression, evading anti-tumor immunity, but PD-1 therapy induced CD8+ T cell infiltration and reduced tumor volume.

Conclusions:

• DNA ligase IV (LIG4) inhibition effectively reduces prostate cancer growth and stemness.
• LIG4 inhibition sensitizes prostate cancers to immune checkpoint inhibition, enhancing anti-tumor immune responses.