PI3Kβ controls immune evasion in PTEN-deficient breast tumours

Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types(1). PTEN is the major negative regulator of PI3K signalling. The PI3K beta isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3K beta 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 PI3K beta led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3K beta 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 PI3K beta 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 PI3K beta controls immune escape in PTEN-null tumours, providing a rationale for combining PI3K beta inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.