Prostate cancers generally lack T cell infiltration and display resistance to immune checkpoint therapies (ICT). We found that intermittent but not daily dosing of PI3Kapha/beta/gamma inhibitor BAY1082439 on a Pten-null spontaneous prostate cancer model could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts Pten-null cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNalpha/gamma pathway activation, B2M expression and CXCL10/CCL5 secretion. Together with its preferential Treg inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells. Once primed, tumors remain as T cell-inflamed and become responsive to anti-PD-1 therapy. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT.

中文翻译：

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通过顺序间歇性抗PI3Ka / b /δ和抗PD-1治疗克服对PTEN无效的前列腺癌免疫检查点治疗的耐药性

前列腺癌通常缺乏T细胞浸润，并显示出对免疫检查点疗法（ICT）的抵抗力。我们发现间歇性而非每日剂量的PI3Kapha /β/γ抑制剂BAY1082439在无Pten的自发性前列腺癌模型上可以克服ICT耐药性并在体内释放CD8 + T细胞依赖性抗肿瘤免疫力。从机制上讲，BAY1082439通过促进IFNalpha /γ途径激活，B2M表达和CXCL10 / CCL5分泌，将无Pten癌细胞固有免疫抑制转化为免疫刺激。与其优先的Treg抑制活性一起，BAY1082439促进肿瘤相关CD8 + T细胞的克隆扩增。一旦引发，肿瘤就保持为T细胞发炎状态，并对抗PD-1治疗产生反应。