The Role of Myeloid-Derived Suppressor Cells in Resistance to Bipolar Androgen Therapy in Patients with Advanced Prostate Cancer

前列腺癌患者对标准护理策略产生抵抗力，进展为晚期疾病和 导致每年35万人死亡。获得性耐药是由雄激素受体(AR)增加所介导的 表达，我们正在开发一种“双相雄激素”疗法(BAT)循环血清睾酮从 超生理学至接近去势水平，分别对高表达AR和低表达AR的细胞产生最大毒性。 BAT是治疗去势耐药前列腺癌的一种有效、安全、独特的治疗方法。 患者改善生活质量，产生生化和客观反应，并使肿瘤对 AR抑制剂。我们最近的一项临床试验(NCT03554317)的数据显示，前列腺肿瘤细胞产生 BAT后的炎性细胞因子和从这种治疗中受益最多的患者有丰富的 肿瘤中的炎性转录信号。因此，尽管它的概念是一种“靶向”疗法，我们的 对蝙蝠的了解已经扩大到考虑它对免疫系统的影响，这似乎对 成功。利用这一未被认识到的潜力，弥合患者之间的差距 不是从这一新策略出发，我们以前和 在用BAT治疗后，以确定它在免疫细胞中诱导的变化。我们的观察表明蝙蝠 治疗不良患者的单核细胞-髓系来源抑制细胞(M-MDSCs)扩增 回应。M-MDSCs的丰富与治疗效果降低之间的关系 文献中的先例，即睾丸激素抑制巨噬细胞的促炎表型，加上 炎症反应在控制BAT后肿瘤生长中的关键作用，将我们引向假说 BAT诱导的M-MDSCs数量增加限制了抗肿瘤免疫，从而降低了治疗效果 功效。为了验证这一假设，我们提出了三个目标：(1)我们将表征转移性CRPC的PBMC 接受BAT治疗的患者利用下一代测序识别M-MDSCs中的转录特征 与治疗反应和模型M-MDSC肿瘤植入相关，因为这些细胞在 对免疫抑制的肿瘤微环境；(2)我们将使用高维流式细胞术来 证明免疫抑制的M-MDSCs是由BAT诱导的，而不是由标准护理治疗诱导的 患者的独立队列，并通过暴露隔离的人类来描述这种诱导背后的机制 外周血单核细胞体外培养至超生理水平的睾酮；(3)我们将利用小鼠前列腺癌模型 目的：评价骨髓间充质干细胞耗竭联合BAT的治疗效果。这一跨领域的协作努力 计算生物学、肿瘤学和髓系细胞生物学的学科将建立一个详细的理解 关于BAT如何重新编程肿瘤免疫并确定M-MDSCs的扩张是否支持对BAT的抵抗力， 从而在未来的临床试验设计中提供了提高治疗效果的目标。

Prostate cancer patients acquire resistance to standard-of-care strategies progressing to advanced disease and resulting in 350,000 yearly deaths. As acquired resistance is mediated by increased androgen receptor (AR) expression, we are developing a “Bipolar Androgen” therapy (BAT) cycling serum testosterone from supraphysiological to near-castrate levels, maximizing toxicity to high and low AR-expressing cells respectively. BAT is a clinically effective, safe and unique approach to treat castration-resistant prostate cancer (CRPC) patients that improves quality of life, produces biochemical and objective responses, and re-sensitizes tumors to AR inhibitors. Our data from a recent clinical trial (NCT03554317) shows that prostate tumor cells produce inflammatory cytokines following BAT, and patients who benefited most from this therapy have an enriched inflammatory transcriptional signature in tumors. Thus, despite its conception as a “targeted” therapy, our understanding of BAT has broadened to consider its effects on the immune system, which appears critical for success. To capitalize on this unappreciated potential and bridge the gap between patients who benefitted or not from this novel strategy, we characterized patient peripheral blood mononuclear cells (PBMCs) before and after treatment with BAT to define the changes it induces in immune cells. Our observations indicate that BAT elicits the expansion of monocytic-myeloid derived suppressor cells (M-MDSCs) in patients with poor therapy responses. The association between the abundance of M-MDSCs and reduced therapeutic efficacy, the precedent in the literature that testosterone dampens the pro-inflammatory phenotype of macrophages, plus the critical role of the inflammatory response in controlling tumor growth following BAT, lead us to the hypothesis that increased numbers of M-MDSCs induced by BAT restrict antitumor immunity leading to reduced therapeutic efficacy. To test this hypothesis, we propose three aims: (1) we will characterize PBMCs from metastatic CRPC patients treated with BAT utilizing next generation sequencing, to identify transcriptional signatures in M-MDSCs that are associated with therapeutic response and model M-MDSC tumor engraftment as these cells contribute to the immunosuppressive tumor microenvironment; (2) we will use high dimensional flow cytometry to demonstrate that immunosuppressive M-MDSCs are induced by BAT and not by standard-of-care therapy in an independent cohort of patients, and describe the mechanism behind this induction by exposing isolated human PBMCs in vitro to supraphysiological levels of testosterone; (3) we will utilize mouse models of prostate cancer to assess the therapeutic benefit of M-MDSC depletion in combination with BAT. This collaborative effort across the disciplines of computational biology, oncology, and myeloid cell biology, will build a detailed understanding of how BAT reprograms tumor immunity and determine if M-MDSCs expansion underpins resistance to BAT, thus providing a target to improve therapeutic efficacy in the design of future clinical trials.