PI3Kß controls immune evasion in PTEN-deficient breast tumors

Loss 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 PI3Kß isoform has been shown to play an important role in PTEN-deficient tumors, but the mechanisms underlying the importance of PI3Kß 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 PI3Kß led to a robust anti-tumor immune response that abrogated tumor growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kß 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 PI3Kß 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 PI3Kß controls immune escape in PTEN-null tumors, providing a rationale for combining PI3Kß inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer. Overall design: Comparative gene expression profiling analysis of RNA-seq data for genetic or pharmacological PI3Kß blockade, STAT3 silencing, or STAT3 activation in PTEN-deficient breast/mammary tumors.