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.

前列腺癌患者对发展为晚期疾病的标准治疗策略产生耐药性