Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer

The kinase PI(3)Kδ is shown to be required for the immunosuppressive function of regulatory T cells; inactivation of PI(3)Kδ in these cells leads to enhanced cytotoxic T-cell function and restricts tumour growth and metastasis in a variety of mouse tumour models. This paper shows that the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) is critically required for the immunosuppressive function of regulatory T (Treg) cells. Inactivation of p110δ in Treg cells leads to enhanced cytotoxic T-cell function and restricts tumour growth and metastasis in a variety of mouse tumour models. This finding identifies p110δ as a druggable kinase target for which inhibition boosts the cancer-suppressive potential of the immune system. Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias1,2. As p110δ is primarily expressed in leukocytes3, drugs against p110δ have not been considered for the treatment of solid tumours4. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.