Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

We aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC. Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic and proteomic profiling, or ex vivo co-culture studies. Single-cell RNAseq on human mCRPC samples was performed using 10X Genomics platform.

本研究旨在阐明前列腺癌对雄激素剥夺治疗（Androgen Deprivation Therapy, ADT）及PI3K-AKT轴阻断的耐药机制，并开发合理的联合治疗策略，以有效治疗转移性去势抵抗性前列腺癌（metastatic Castration-resistant Prostate Cancer, mCRPC）的该分子亚型。本研究通过超声评估，选取成瘤体积达150~200 mm³的前列腺特异性PTEN/p53缺陷基因工程小鼠（Genetically Engineered Mouse, GEM），分别给予单药或联合给药方案：雄激素剥夺治疗（ADT，地加瑞克（degarelix））、PI3K抑制剂（copanlisib）或抗PD-1抗体（anti-PD-1 antibody, aPD-1）；实验期间通过磁共振成像（Magnetic Resonance Imaging, MRI）监测肿瘤生长，随后采集肿瘤样本开展免疫组学、转录组学、蛋白质组学分析，或离体共培养实验。本研究采用10X基因组学（10X Genomics）平台，对人类转移性去势抵抗性前列腺癌样本开展单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。