| Autor: |
Bergholz, Johann S., Wang, Qiwei, Wang, Qi, Ramseier, Michelle, Prakadan, Sanjay, Wang, Weihua, Fang, Rong, Kabraji, Sheheryar, Zhou, Qian, Gray, G. Kenneth, Abell-Hart, Kayley, Xie, Shaozhen, Guo, Xiaocan, Gu, Hao, Von, Thanh, Jiang, Tao, Tang, Shuang, Freeman, Gordon J., Kim, Hye-Jung, Shalek, Alex K. |
| Zdroj: |
Nature; May2023, Vol. 617 Issue 7959, p139-146, 8p |
| Abstrakt: |
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.A mouse model of invasive breast cancer in which Pten and Trp53 are simultaneously inactivated links PTEN loss with STAT3 activation and indicates that immune escape in PTEN-null tumours is mediated by PI3Kβ. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
Full text from SpringerLink