Aggressive prostate cancer of African Americans is correlated with regulation of Immunoregulatory Genes in stroma

非裔美国人的侵袭性前列腺癌与基质中免疫调节基因的调节相关

• 批准号: 10170756
• 负责人: Farah Bakhshian Rahmatpanah
• 金额: $ 7.85万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170756
• 关键词: 2019-nCoV; Accounting; Administrative Supplement; Affect; African American; Age; American; Antigen-Presenting Cells; Antiviral Agents; Antiviral Response; Applications Grants; Area; Ascorbic Acid; Biological Assay; COVID-19; Cancer Patient; Cell Culture Techniques; Cells; Centers for Disease Control and Prevention (U.S.); Combined Modality Therapy; Dendritic Cells; Dendritic cell activation; Diagnosis; Disease; Disease Outbreaks; Disease Progression; Disseminated Malignant Neoplasm; Endogenous Retroviruses; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Ethnic Origin; European; Exposure to; Fibroblasts; Genes; Genetic; Genetic Transcription; IRF3 gene; Immune; Immune response; Immune system; Immunologist; Infection; Interferons; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Messenger RNA; Methyltransferase; New York City; Nonmetastatic; Nucleic Acids; Outcome; PF4 Gene; Pathway interactions; Patients; Play; Population; Process; Production; Prostate; RNA; Race; Regulation; Resistance; Resources; Role; Severe Acute Respiratory Syndrome; Severity of illness; Socioeconomic Factors; Solid Neoplasm; Stromal Cells; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor-infiltrating immune cells; United States National Institutes of Health; Viral; Virus; Virus Diseases; anti-tumor immune response; base; cancer health disparity; comorbidity; comorbidity Index; ethnic disparity; experience; immunoregulation; improved outcome; infection rate; inhibitor/antagonist; men; mimicry; mortality; neoplasm resource; new therapeutic target; nucleotide analog; outcome forecast; parent grant; pathogenic virus; prostate cancer progression; racial disparity; racial diversity; response; transcription factor; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Recent studies indicate that patients with metastatic cancer experience more severe outcomes of SARS- CoV-2 (COVID-19) virus infections compared to those with non-metastatic carcinomas and patients without cancer, possibly due to their compromised immune systems. According to the Centers for Disease Control and Prevention, African Americans (AA) suffer from the virus at higher rates than the European American (EA) population of the US. The mechanisms of how ethnicity contributes to higher SARS-CoV-2 infection rates and increased disease severity are unknown, but genetic/epigenetic components (in addition to socioeconomic factors) often play a role in disease progression and response to therapies. As an example, prostate cancer (PCa) in AA is diagnosed at an earlier median age and in a more advanced stage than PCa of EA, with poorer prognosis and significantly higher mortality. These differences persist even after accounting for socioeconomic and environmental factors. In our parent grant, NIH/NCI R01CA226570 “Aggressive prostate cancer of African Americans is correlated with regulation of immunoregulatory genes in stroma”, we propose an epigenetic control of the antiviral immune response pathways in prostate stromal cells as one of the reasons for differences in prostate cancer progression among patients. We observed that the antiviral immune responses to endogenous retroviruses (ERVs) activate type 1 interferons (IFNs) that in turn increase transcription of interferon-stimulated genes (ISGs) in tumor-adjacent stroma, as measured by RNA levels in tumor-adjacent cancer-associated fibroblasts (CAFs). This stimulation proceeds more strongly in EA than in AA. Furthermore, mRNA markers of activated dendritic cells (DCs), which are part of the antitumor immune response, were also more prevalent in EA than in AA tumor-adjacent stroma. These processes have each been associated with improved outcome in several solid tumors, making this antiviral pathway a potential target for an activation therapy. DCs are immune cells that produce IFNs and can have antitumor as well as antiviral activity, including anti-SARS-CoV-2. In this administrative supplement application, we hypothesize that cancer-associated alterations in the function of DCs affect the response to SARS-Co-V2 among cancer patients, especially in those with aggressive disease. These alterations may be different (and have different outcomes) in AA patients compared to EA. We further hypothesize that antiviral immune response pathways in cancer patients infected with SARS-CoV-2 can be activated using the nucleotide analog 5AzaC, a methyltransferase inhibitor, in combination with vitamin C, which increases the viral mimicry induced by 5AzaC. We will test our hypotheses in two aims. First, we will investigate whether and how the antiviral immune response to SARS-CoV-2 is exacerbated by race and cancer, and second, we will determine whether AA and EA CAFs treated with a combination of 5AzaC and vitamin C can enhance antiviral responses of DCs to SARS-CoV-2. Impact: In addition to suppressing tumor growth, the proposed immune-stimulating combination therapy with 5AzaC and vitamin C may also activate immune responses to SARS-CoV-2 infection by galvanizing anti- viral immune response pathways in both the tumor and the DCs.

项目总结/摘要 最近的研究表明，转移性癌症患者经历了SARS更严重的后果- CoV-2（COVID-19）病毒感染与非转移性癌患者和未发生 癌症，可能是由于他们的免疫系统受损。根据疾病控制中心和 预防，非洲裔美国人（AA）比欧洲裔美国人（EA）遭受病毒的比率更高 美国的人口。种族如何导致SARS-CoV-2感染率升高的机制， 增加的疾病严重程度是未知的，但遗传/表观遗传成分（除了社会经济因素）， 因素）通常在疾病进展和对治疗的反应中起作用。例如，前列腺癌 (PCa)AA的诊断中位年龄较早，比EA的PCa处于更晚期， 预后和显著更高的死亡率。即使在考虑了社会经济因素后， 和环境因素。在我们的母基金中，NIH/NCI R 01 CA 226570“非洲人侵袭性前列腺癌” 美国人与基质中免疫调节基因的调节相关”，我们提出了一种表观遗传控制 前列腺基质细胞中的抗病毒免疫应答途径是前列腺基质细胞中抗病毒免疫应答差异的原因之一。 前列腺癌患者中的进展。我们观察到内源性抗病毒免疫应答 逆转录病毒（ERV）激活1型干扰素（IFN），反过来增加干扰素刺激的转录。 肿瘤邻近基质中的ISG基因，如通过肿瘤邻近癌症相关组织中的RNA水平所测量的。 成纤维细胞（CAF）。这种刺激在EA中比在AA中进行得更强烈。此外， 活化的树突状细胞（DC），这是抗肿瘤免疫反应的一部分，也更普遍， EA比AA肿瘤相邻间质中的高。这些进程都与改善成果有关， 几种实体瘤，使这种抗病毒途径成为激活疗法的潜在靶点。 DC是产生IFN的免疫细胞，并且可以具有抗肿瘤以及抗病毒活性，包括 抗SARS-CoV-2在这份行政补充申请中，我们假设癌症相关的 DC功能的改变影响癌症患者对SARS-Co-V2的反应，特别是那些 侵袭性疾病。这些改变在AA患者中可能是不同的（并且具有不同的结果 与EA相比。我们进一步假设癌症患者的抗病毒免疫反应途径是感染 可以使用核苷酸类似物5AzaC（一种甲基转移酶抑制剂）激活SARS-CoV-2， 与维生素C组合，其增加由5AzaC诱导的病毒模拟。 我们将在两个目标中检验我们的假设。首先，我们将研究抗病毒药物是否以及如何 对SARS-CoV-2的免疫反应会因种族和癌症而加剧，其次，我们将确定 用5AzaC和维生素C的组合处理的AA和EA CAF是否可以增强抗病毒能力 DCs对SARS-CoV-2的反应。 影响：除了抑制肿瘤生长外，拟议的免疫刺激联合疗法 5AzaC和维生素C也可能通过激发抗SARS-CoV-2感染的免疫反应， 肿瘤和DC中的病毒免疫应答途径。