Fig. 6

Model of pharmacological reversion of T-regs immunosuppression, improved CD8+ T-cells activation and memory by PI3Kα/δ isoform inhibition. Previous studies have suggested anti-tumor effects of PI3Kδ inhibitors resulting in anti-tumor immunity mainly via tumor T-regs suppression and release of partially suppressed CD8 cytotoxic T-cells (CD8⁺) to target tumor cells [11, 13, 20]. Here we show that PI3Kδ inhibitors, more specifically a AZD8835, an equipotent PI3Kα/δ inhibitor, can directly potentiate CD8⁺ T-cells activation in a dose-dependent manner, dissociated of continuous T-regs suppression in vivo. The direct effects are likely driven via an autocrine IL-2 signaling axis leading to improved CD8⁺ T-cell survival and activation in primary ex vivo and in vivo experiments. Moreover, we have shown that durable responses could be achieved at an intermittent dose schedule along with increase memory T-cell formation. Moreover, AZD8835 promoted broader changes in other tumor immune cells that could contribute to enhanced efficacy (e.g., MDSCs, Macrophages and NK cells)