PI3Kβ controls immune evasion in PTEN-deficient breast tumours

Johann S. Bergholz, Qiwei Wang, Qi Wang, Michelle Ramseier, Sanjay Prakadan, Weihua Wang, Rong Fang, Sheheryar Kabraji, Qian Zhou, G. Kenneth Gray, Kayley Abell-Hart, Shaozhen Xie, Xiaocan Guo, Hao Gu, Thanh Von, Tao Jiang, Shuang Tang, Gordon J. Freeman, Hye-Jung Kim, Alex K. Shalek, Thomas M. Roberts () and Jean J. Zhao ()
Additional contact information
Johann S. Bergholz: Dana-Farber Cancer Institute
Qiwei Wang: Dana-Farber Cancer Institute
Qi Wang: Dana-Farber Cancer Institute
Michelle Ramseier: Broad Institute of Harvard and MIT
Sanjay Prakadan: Broad Institute of Harvard and MIT
Weihua Wang: Dana-Farber Cancer Institute
Rong Fang: Dana-Farber Cancer Institute
Sheheryar Kabraji: Dana-Farber Cancer Institute
Qian Zhou: Fudan University Shanghai Cancer Center
G. Kenneth Gray: Harvard Medical School
Kayley Abell-Hart: Dana-Farber Cancer Institute
Shaozhen Xie: Dana-Farber Cancer Institute
Xiaocan Guo: Dana-Farber Cancer Institute
Hao Gu: Dana-Farber Cancer Institute
Thanh Von: Dana-Farber Cancer Institute
Tao Jiang: Dana-Farber Cancer Institute
Shuang Tang: Dana-Farber Cancer Institute
Gordon J. Freeman: Dana-Farber Cancer Institute
Hye-Jung Kim: Dana-Farber Cancer Institute
Alex K. Shalek: Broad Institute of Harvard and MIT
Thomas M. Roberts: Dana-Farber Cancer Institute
Jean J. Zhao: Dana-Farber Cancer Institute

Nature, 2023, vol. 617, issue 7959, 139-146

Abstract: Abstract Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3Kβ led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.

Date: 2023
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DOI: 10.1038/s41586-023-05940-w

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