Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Combining immune checkpoint therapy (ICT) with targeted therapies offers potential for lasting anti-cancer effects.
• PI3K inhibitors face challenges in combination therapies due to complex effects on cancer and immune cells.
• PI3K pathway dysregulation is common in various cancers, including prostate cancer.

Purpose of the Study:

• To investigate the efficacy of intermittent versus daily dosing of a PI3K inhibitor in overcoming ICT resistance.
• To elucidate the mechanisms by which PI3K inhibition impacts the tumor microenvironment and anti-tumor immunity.
• To evaluate the potential of intermittent PI3K inhibition to enhance responses to anti-PD-1 therapy.

Main Methods:

• Utilized Pten-null prostate cancer models in vivo.
• Administered a PI3Kα/β/δ inhibitor (BAY1082439) with intermittent and daily dosing schedules.
• Assessed anti-tumor immunity, including CD8+ T cell responses, IFN pathway activation, and cytokine secretion.
• Evaluated tumor responsiveness to anti-PD-1 therapy.

Main Results:

• Intermittent dosing of BAY1082439, but not daily dosing, overcame ICT resistance in Pten-null prostate cancer models.
• PI3K inhibition promoted IFNα/IFNγ pathway activation, β2-microglubin expression, and CXCL10/CCL5 secretion.
• Intermittent PI3K inhibition preferentially inhibited regulatory T cells, promoting CD8+ T cell expansion.
• Tumors became T cell-inflamed and responsive to anti-PD-1 therapy, demonstrating durable effects.

Conclusions:

• Intermittent PI3K inhibition effectively converts immunosuppressive, "cold" tumors into T cell-inflamed, immunologically responsive tumors.
• This approach alleviates cancer cell-intrinsic immunosuppressive activity and enhances anti-tumor immunity.
• Intermittent PI3K inhibition represents a promising strategy for combination with ICT to achieve durable anti-cancer responses.