Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Department of Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida.
Clin Cancer Res. 2023 May 15;29(10):1952-1968. doi: 10.1158/1078-0432.CCR-22-3350.
Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, 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 RNA sequencing on human mCRPC samples was performed using 10X Genomics platform.
Coclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.
Immunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.
磷酸酶和张力蛋白同源物（PTEN）功能丧失发生在大约 50%的转移性去势抵抗前列腺癌（mCRPC）患者中，与预后不良以及对标准治疗和免疫检查点抑制剂的反应性差有关。虽然 PTEN 功能丧失会使 PI3K 信号过度激活，但联合使用 PI3K/AKT 通路和雄激素剥夺疗法（ADT）在临床试验中显示出有限的抗癌疗效。在这里，我们旨在阐明对 ADT/PI3K-AKT 轴阻断的耐药机制，并制定合理的联合策略来有效治疗这种 mCRPC 的分子亚型。
通过超声评估，建立了前列腺特异性 PTEN/p53 缺陷的基因工程小鼠（GEM），肿瘤大小为 150-200mm3，然后用 ADT（degarelix）、PI3K 抑制剂（copanlisib）或抗 PD-1 抗体（aPD-1）单独或联合治疗，并通过 MRI 监测肿瘤，收获进行免疫、转录组和蛋白质组分析，或进行体外共培养研究。使用 10X Genomics 平台对人 mCRPC 样本进行单细胞 RNA 测序。
PTEN/p53 缺陷 GEM 的临床前试验表明，PD-1 表达的肿瘤相关巨噬细胞（TAM）的募集会破坏 ADT/PI3Ki 联合治疗诱导的肿瘤控制。将 aPD-1 加入 ADT/PI3Ki 联合治疗中，导致抗癌反应增加约 3 倍，这主要归因于 TAM 的作用。从机制上讲，PI3Ki 处理的肿瘤细胞中乳酸产量的减少抑制了 TAM 中的组蛋白乳酰化，导致其抗癌吞噬作用被激活，这种激活作用被 ADT/aPD-1 治疗增强，并被 Wnt/β-catenin 通路的反馈激活所阻断。mCRPC 患者活检样本的单细胞 RNA-seq 分析显示，高糖酵解活性与 TAM 吞噬作用抑制之间存在直接相关性。
逆转乳酸和 PD-1 介导的 TAM 免疫抑制的免疫代谢策略，与 ADT 联合使用，值得进一步在 PTEN 缺陷型 mCRPC 患者中进行研究。
