PI3Kβ controls immune evasion in PTEN-deficient breast tumours

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Loss of the PTEN tumor suppressor is a common driver in many cancers.
• PTEN negatively regulates PI3K signaling, with PI3Kβ implicated in PTEN-deficient tumors.
• Mechanisms linking PI3Kβ activity to tumor progression in PTEN-loss cancers are not fully understood.

Purpose of the Study:

• To investigate the role of PI3Kβ in PTEN-deficient invasive breast cancer.
• To elucidate the mechanisms by which PI3Kβ influences anti-tumor immunity.
• To evaluate the therapeutic potential of PI3Kβ inhibition, alone and in combination with immunotherapy.

Main Methods:

• Utilized a syngeneic genetically engineered mouse model of invasive breast cancer with Pten and Trp53 ablation.
• Assessed the impact of genetic PI3Kβ inactivation on tumor growth in immunocompetent and immunodeficient mice.
• Investigated downstream signaling pathways, including STAT3, and immune stimulatory molecule expression.
• Evaluated the efficacy of pharmacological PI3Kβ inhibition and its combination with immunotherapy.

Main Results:

• Genetic inactivation of PI3Kβ induced robust anti-tumor immune responses and abrogated tumor growth in immunocompetent mice.
• PI3Kβ inactivation reduced STAT3 signaling and increased immune stimulatory molecule expression in PTEN-null tumors.
• Pharmacological PI3Kβ inhibition elicited anti-tumor immunity and synergized with immunotherapy.
• Mice achieving complete response showed immune memory and rejected subsequent tumor re-challenge.

Conclusions:

• PI3Kβ controls immune escape in PTEN-null tumors by modulating STAT3 signaling and immune responses.
• Combining PI3Kβ inhibitors with immunotherapy offers a promising therapeutic strategy for PTEN-deficient breast cancer.
• This study reveals a molecular link between PTEN loss, STAT3 activation, and immune evasion in cancer.