PAK4 inhibition improves PD-1 blockade immunotherapy.

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Primary resistance to programmed cell death protein 1 (PD-1) blockade in cancer is often due to a lack of tumor-infiltrating immune cells.
• Cancer cell-intrinsic mechanisms may actively prevent T cell infiltration, suggesting that targeting these mechanisms could synergize with immunotherapy.

Purpose of the Study:

• To investigate the role of p21-activated kinase 4 (PAK4) in T cell exclusion and resistance to PD-1 blockade.
• To determine if inhibiting PAK4 can enhance anti-tumor immune responses.

Main Methods:

• Analysis of PAK4 expression in human tumor biopsies with varying T cell and dendritic cell infiltration.
• Utilizing mouse models with genetic deletion of PAK4 to assess T cell infiltration and response to PD-1 blockade.
• Evaluating the combination of anti-PD-1 therapy with a PAK4 inhibitor (KPT-9274) in preclinical cancer models.

Main Results:

• PAK4 was found to be enriched in tumors with low T cell and dendritic cell infiltration, correlating with resistance to PD-1 blockade.
• Genetic deletion of PAK4 significantly increased CD8 T cell infiltration into tumors.
• The combination of anti-PD-1 therapy and the PAK4 inhibitor KPT-9274 demonstrated improved anti-tumor efficacy compared to anti-PD-1 alone.

Conclusions:

• High PAK4 expression is associated with reduced T cell and dendritic cell infiltration and primary resistance to PD-1 blockade.
• PAK4 inhibition represents a potential strategy to overcome resistance to checkpoint inhibitor immunotherapy by increasing T cell infiltration.