Disrupting the Prostate Tumor Microenvironment in African American Men to Promote Response to Immuno-Modulatory Therapy

破坏非裔美国男性的前列腺肿瘤微环境以促进对免疫调节治疗的反应

• 批准号: 10521913
• 负责人: Kosj Yamoah
• 金额: $ 68.46万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521913
• 关键词: Affect; African American; American; Apoptosis; Area; Biochemical; Biological; Biological Factors; Biological Response Modifiers; Biomedical Engineering; Biopsy Specimen; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Biology; Caring; Cell Communication; Cell Line; Cells; Characteristics; Chemotactic Factors; Clinical; Clinical Research; Combination immunotherapy; Comparative Genomic Analysis; DNA Damage; DNA Repair; Data; Data Set; Distant Metastasis; Dose; Epithelial Cells; European; Gene Expression; Gene set enrichment analysis; Genes; Genomics; Goals; Immune; Immunomodulators; Immunosuppression; Immunotherapy; Incidence; Interferons; Interleukins; Intervention; Investigation; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Medical; Modeling; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Pattern; Phase; Phenotype; Play; Population; Prostate; Prostatic Neoplasms; Race; Radiation Tolerance; Radiation therapy; Recurrence; Reduce health disparities; Resistance; Risk; Role; STING1 gene; Signal Transduction; Socioeconomic Factors; Socioeconomic Status; Specimen; Stimulator of Interferon Genes; TNF gene; Therapeutic; Tissues; Tumor-infiltrating immune cells; Work; advanced disease; androgen deprivation therapy; cancer health disparity; cell type; clinically relevant; cohort; cytokine; differential expression; disparity reduction; experience; gene repair; genomic biomarker; health disparity; immunological intervention; immunomodulatory therapies; immunoregulation; improved outcome; men; migration; novel; novel therapeutic intervention; personalized immunotherapy; phase 2 study; racial difference; racial disparity; radiation response; response; sample archive; tertiary lymphoid organ; transcriptome; treatment response; tumor; tumor microenvironment; tumor-immune system interactions; validation studies; whole genome

PROJECT SUMMARY African-American men (AAM) are known to present with more advanced disease resulting from both biological and socio-economic factors. Specific to biological factors, there is emerging data suggesting that AAM with prostate cancer (PCa) have an immunosuppressive tumor immune microenvironment (TIME) characterized by low DNA damage repair and high IFN-response pathway. Consequently, immune mediators and DNA damage response may play a major role in PCa biology in AAM. The mechanism and potential therapeutic benefit of combining immune modulators to disrupt the TIME for therapeutic gain in AAM with PCa is an area of active investigation. Furthermore, whether immune-modulatory therapy has differential effects on immune cell-types within the TIME of AAM vs. European-American men (EAM) is currently unknown. The proposed studies in this application will first computationally deconvolute the TIME of AAM and EAM highlighting the functional characteristics of key immune cells and soluble immune mediators. To overcome the limitation of cell line models, we will use a novel bioengineered platform to study tumor-immune interactions and mechanistically define how differences in the STING-IFN response pathway impacts response and/or resistance to immune modulators. Next, we will evaluate how differences in the TIME from AAM and EAM may affect the therapeutic response to immune-modulators using patient-derived explants – a unique ex-vivo model from fresh viable surgical specimens. Importantly, we will also validate these results in serial patient-derived biopsies and blood samples that have been collected as part of a phase II clinical study combining ADT, RT and immunotherapy (NCT03543189). These studies will unravel mechanisms that can be exploited to identify new therapeutic approaches to improve outcomes in AAM with PCa.

项目概要 众所周知，非洲裔美国男性 (AAM) 会因生物因素而出现更严重的疾病。 具体到生物因素，有新的数据表明 AAM 与 前列腺癌 (PCa) 具有免疫抑制性肿瘤免疫微环境 (TIME)，其特征为 低 DNA 损伤修复和高 IFN 反应途径测试、免疫介质和 DNA 损伤。 AAM 的机制和潜在的治疗益处可能在 PCa 生物学中发挥重要作用。 结合免疫调节剂来破坏 AAM 与 PCa 的治疗效果的时间是一个活跃的领域 此外，免疫调节疗法是否对免疫细胞类型有不同的影响。 AAM 与欧美男性 (EAM) 的时间范围内的差异目前尚不清楚。 应用程序将首先通过计算对 AAM 和 EAM 的 TIME 进行解卷积，突出显示功能 关键免疫细胞和可溶性免疫介质的特性，克服细胞系模型的局限性， 我们将使用一种新颖的生物工程平台来研究肿瘤-免疫相互作用并从机械上定义如何 STING-IFN 反应途径的差异会影响对免疫调节剂的反应和/或抵抗力。 接下来，我们将评估 AAM 和 EAM 的时间差异如何影响治疗反应 使用患者来源的外植体的免疫调节剂——来自新鲜可行手术的独特离体模型 重要的是，我们还将在连续的患者活检和血液样本中验证这些结果。 已收集作为 ADT、RT 和免疫疗法相结合的 II 期临床研究的一部分 (NCT03543189)。这些研究将揭示可用于识别新疗法的机制。 改善 AAM 与 PCa 结果的方法。