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

项目摘要/摘要 最近的研究表明，转移性癌症患者经历了更严重的SARS- 冠状病毒2型(新冠肺炎)感染与非转移性癌症患者和非转移性癌症患者的比较 癌症，可能是由于他们的免疫系统受损。据美国疾病控制和预防中心称 预防方面，非裔美国人(AA)感染病毒的比率高于欧洲裔美国人(EA) 美国的人口。种族如何导致SARS-CoV-2高感染率和 疾病严重性的增加是未知的，但遗传/表观遗传因素(除社会经济因素外 因素)通常在疾病进展和对治疗的反应中发挥作用。举个例子，前列腺癌 与EA的PCA相比，AA的诊断中位年龄更早，且处于更晚期，表现较差 预后和显著更高的死亡率。即使在考虑到社会经济因素后，这些差异仍然存在 以及环境因素。在我们的父母资助中，NIH/NCI R01CA226570“非洲侵袭性前列腺癌” 美国人与间质中免疫调节基因的调节有关“，我们提出表观遗传控制 前列腺癌间质细胞中抗病毒免疫反应途径的研究 前列腺癌在患者中的进展。我们观察到内源性的抗病毒免疫反应 逆转录病毒(ERV)激活1型干扰素(IFN)，进而增加干扰素刺激的转录 癌旁间质中的基因(ISGs)，通过癌旁癌相关组织中的RNA水平来衡量 成纤维细胞(CAF)。这种刺激在电针中比在再生障碍性脑病中进行得更强烈。此外，还发现了一些新的基因标记 活化的树突状细胞(DC)是抗肿瘤免疫反应的一部分，在 在AA瘤旁间质中，EA的表达高于AA癌旁间质。这些过程中的每一个都与改善 几个实体肿瘤，使这一抗病毒途径成为激活治疗的潜在靶点。 树突状细胞是一种免疫细胞，可以产生干扰素，具有抗肿瘤和抗病毒活性，包括 抗SARS-CoV-2。在这个行政补充应用程序中，我们假设与癌症相关 树突状细胞功能的改变影响癌症患者对SARS-Co-V2的反应，尤其是在 患有侵袭性疾病。这些改变在再生障碍性贫血患者中可能是不同的(并且有不同的结果) 与EA相比。我们进一步假设，感染癌症患者中的抗病毒免疫反应途径 对于SARS-CoV-2，可以使用核苷酸类似物5AzaC，一种甲基转移酶抑制剂，在 与维生素C联合使用，可增加5-氮卓酮诱导的病毒模仿性。 我们将在两个目标上检验我们的假设。首先，我们将调查抗病毒药物是否以及如何 对SARS-CoV-2的免疫反应因种族和癌症而加剧，第二，我们将确定 AA和EA CAF联合应用5-氮卓酮和维生素C是否能增强抗病毒作用 DC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 5-氮卓酮和维生素C也可能通过激活抗SARS-CoV-2而激活对SARS-CoV-2的免疫应答 肿瘤和树突状细胞中的病毒免疫反应途径。

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.