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

骨髓源性抑制细胞在晚期前列腺癌患者双极雄激素治疗耐药中的作用

• 批准号: 10648749
• 负责人: Samuel R Denmeade
• 金额: $ 22.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648749
• 关键词: Affect; Aftercare; Androgen Receptor; Androgen Therapy; Androgens; Animal Model; Biochemical; Biological Assay; Biopsy; Cancer Patient; Castration; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical; Clinical Trials; Computational Biology; Conceptions; Coupling; Data; Data Set; Discipline; Disease; Disease Resistance; Effectiveness; Endotoxic Shock; Engraftment; Exposure to; Expression Profiling; Flow Cytometry; Fluorouracil; Future; Gene Expression; Gene Expression Profile; Human; Immune; Immune Tolerance; Immune system; Immunity; Immunologic Markers; Immunosuppression; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innovative Therapy; Interleukin-10; Left; Literature; Lung; Macrophage; Malignant neoplasm of prostate; Mediating; Modeling; Myeloid Cells; Myeloid-derived suppressor cells; Nivolumab; Non-Malignant; Oncology; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Prostate Cancer therapy; Prostatic Neoplasms; Publishing; Quality of life; Resistance; Resistance development; Resolution; Role; Serum; T-Lymphocyte; Technology; Testing; Testosterone; Therapeutic; Toxic effect; Transforming Growth Factor beta; Treatment Efficacy; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Up-Regulation; advanced disease; advanced prostate cancer; androgen deprivation therapy; anti-tumor immune response; arginase; castration resistant prostate cancer; cohort; cytokine; data integration; design; enzalutamide; high dimensionality; improved; inhibitor; monocyte; mouse model; neoplastic cell; next generation sequencing; novel strategies; palliative; participant enrollment; programmed cell death protein 1; programs; prostate cancer cell; prostate cancer model; protein expression; radiological imaging; receptor expression; resistance mechanism; response; sex; single-cell RNA sequencing; standard of care; success; targeted treatment; transcriptome sequencing; treatment response; tumor; tumor growth; tumor-immune system interactions

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.

前列腺癌患者对标准治疗策略产生抵抗，进展为晚期疾病，并且 每年导致 35 万人死亡。由于获得性耐药是由雄激素受体 (AR) 增加介导的 表达，我们正在开发一种“双极雄激素”疗法（BAT），循环血清睾酮 超生理至接近阉割水平，分别对高和低 AR 表达细胞的毒性最大化。 BAT 是一种临床上有效、安全且独特的治疗去势抵抗性前列腺癌 (CRPC) 的方法 改善患者生活质量，产生生化和客观反应，并使肿瘤重新敏感 AR抑制剂。我们最近的一项临床试验 (NCT03554317) 的数据表明，前列腺肿瘤细胞产生 BAT 后炎症细胞因子的减少，从该疗法中受益最大的患者具有丰富的 肿瘤中的炎症转录特征。因此，尽管它的概念是“靶向”治疗，但我们的 对 BAT 的理解已经扩大到考虑其对免疫系统的影响，这对于免疫系统来说似乎至关重要 成功。利用这种未被认识到的潜力并弥合受益或受益患者之间的差距 并非来自这种新策略，我们在之前和之后对患者外周血单核细胞（PBMC）进行了表征 用 BAT 治疗后确定其在免疫细胞中引起的变化。我们的观察表明 BAT 在治疗效果不佳的患者中引起单核细胞骨髓源性抑制细胞 (M-MDSC) 的扩增 回应。 M-MDSC 丰度与治疗效果降低之间的关联 文献中的先例表明睾酮抑制巨噬细胞的促炎表型，加上 BAT 后炎症反应在控制肿瘤生长中的关键作用使我们得出以下假设 BAT 诱导的 M-MDSC 数量增加限制了抗肿瘤免疫，导致治疗效果降低 功效。为了检验这一假设，我们提出了三个目标：（1）我们将表征来自转移性 CRPC 的 PBMC 使用 BAT 治疗的患者利用下一代测序来识别 M-MDSC 中的转录特征 与治疗反应和 M-MDSC 肿瘤移植模型相关，因为这些细胞有助于 免疫抑制肿瘤微环境； (2)我们将使用高维流式细胞术 证明免疫抑制性 M-MDSC 是由 BAT 诱导的，而不是由标准护理治疗诱导的 独立的患者队列，并通过暴露孤立的人类来描述这种诱导背后的机制 PBMC 体外达到超生理水平的睾酮水平； (3)我们将利用前列腺癌的小鼠模型 评估 M-MDSC 消耗与 BAT 联合治疗的疗效。这项跨界合作努力 计算生物学、肿瘤学和骨髓细胞生物学等学科将建立详细的理解 BAT 如何重新编程肿瘤免疫并确定 M-MDSC 扩增是否支持 BAT 耐药性， 从而为未来临床试验设计中提高治疗效果提供目标。