PI3Kβ controls immune evasion in PTEN-deficient breast tumours

Nature. 2023 May;617(7959):139-146. doi: 10.1038/s41586-023-05940-w.

Johann S Bergholz ^# ¹ ² ³, Qiwei Wang ^# ¹ ² ³, Qi Wang ^# ¹ ⁴, Michelle Ramseier ³ ⁵ ⁶, Sanjay Prakadan ³ ⁵ ⁶, Weihua Wang ¹, Rong Fang ¹ ⁷, Sheheryar Kabraji ¹ ⁸ ⁹, Qian Zhou ¹⁰, G Kenneth Gray ¹¹, Kayley Abell-Hart ¹, Shaozhen Xie ¹ ², Xiaocan Guo ¹ ², Hao Gu ¹ ², Thanh Von ¹, Tao Jiang ¹, Shuang Tang ¹ ² ¹⁰, Gordon J Freeman ⁸, Hye-Jung Kim ¹² ¹³, Alex K Shalek ³ ⁵ ⁶, Thomas M Roberts ¹⁴ ¹⁵, Jean J Zhao ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
4 Geode Therapeutics, Inc., Boston, MA, USA.
5 Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
6 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
7 Ningbo Clinical Pathology Diagnosis Center, Ningbo, P. R. China.
8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
9 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
10 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.
11 Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
12 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
13 Department of Immunology Discovery, Genentech, South San Francisco, CA, USA.
14 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
15 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
16 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
17 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
18 Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
# Contributed equally.

PMID: 37076617 DOI: 10.1038/s41586-023-05940-w

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.

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