Bergholz, JohannWang, QiweiWang, QiRamseier, MichellePrakadan, SanjayWang, WeihuaFang, RongKabraji, SheheryarZhou, QianGray, G. KennethAbell-Hart, KayleyXie, ShaozhenGuo, XiaocanGu, HaoVon, ThanhJiang, TaoTang, ShuangFreeman, Gordon J.Kim, Hye-JungShalek, Alex K.Roberts, Thomas M.Zhao, Jean J.2023-08-142023-04-19Bergholz, Johann, Qiwei Wang, Qi Wang, Michelle Ramseier, Sanjay Prakadan, Weihua Wang, Rong Fang et al. "PI3Kβ controls immune evasion in PTEN-deficient breast tumours." Nature 617, no. 7959 (2023): 139-146. DOI: 10.1038/s41586-023-05940-w0028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376757Loss of the PTEN tumor suppressor is one of the most common oncogenic drivers across all cancer types. PTEN is the major negative regulator of phosphoinositide-3 kinase (PI3K) signaling. Notably, the PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumors, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Using a syngeneic genetically-engineered mouse (GEM) model of invasive breast cancer driven by concurrent ablation of Pten and Trp53 (p53), we showed that genetic inactivation of PI3Kβ led to a robust anti-tumor immune response that abrogated tumor growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signaling and increased expression of immune stimulatory molecules, thereby promoting anti-tumor immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumor immunity, and synergized with immunotherapy to inhibit tumor growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumors 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 tumors, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.en-USMultidisciplinaryJournal Article2023-08-1410.1038/s41586-023-05940-w