Ethnicity-determined T cell responses and GARP/TGFbeta1 signaling in prostate cancer

前列腺癌中种族决定的 T 细胞反应和 GARP/TGFbeta1 信号传导

• 批准号: 10358338
• 负责人: Anshu Agrawal
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358338
• 关键词: Accounting; Affect; African American; Age; American; Anticoagulants; Aspirin; Atrial Fibrillation; Autologous; Autologous Tumor Cell; Benign; Biological Factors; CD8-Positive T-Lymphocytes; Cancer Patient; Cancer Vaccines; Carcinoma; Cells; Clinical Trials; Coculture Techniques; Complex; Cryopreservation; Data; Development; Dissection; Distant; Docking; ERG gene; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Ethnic group; European; Fibroblasts; Flow Cytometry; Formalin; Gene Fusion; Genetic; Gleason Grade for Prostate Cancer; Goals; Histology; Human; Immune; Immune Evasion; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunobiology; Immunohistochemistry; Immunologics; Immunosuppression; Immunotherapy; Incidence; Infiltration; Integrins; Interferons; LRRC32 gene; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Modeling; Mutation; Organoids; PTEN gene; Paraffin Embedding; Patients; Peripheral Blood Lymphocyte; Persons; Plasma; Play; Prostatic Neoplasms; Provenge; Race; Regulatory T-Lymphocyte; Reporting; Resistance; Resources; Role; Safety; Signal Transduction; Socioeconomic Factors; Stains; Stroke prevention; T cell response; T-Lymphocyte; Testing; Tissue Embedding; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Tumor Escape; Tumor-Derived; Tumor-infiltrating immune cells; Variant; anti-CTLA4; anti-PD-1; cancer health disparity; castration resistant prostate cancer; checkpoint therapy; clinically relevant; cytotoxic CD8 T cells; effector T cell; health disparity; improved outcome; individual patient; men; mortality; mouse model; neoplastic cell; novel strategies; overexpression; prostate cancer progression; racial and ethnic; receptor; response; side effect; tool; tumor; tumor growth; tumor microenvironment; tumor xenograft

Project Summary Prostate cancer (PCa) incidence and mortality rates are the highest in African American (AA) men compared to any other racial/ethnic population. These differences persist even after accounting for socioeconomic factors, suggesting genetics and unknown biological factors may contribute to PCa health disparities. However, common genetic alterations, such as TMPRRSS2-ERG gene fusions and PTEN loss, were found to occur much less frequently in AA PCa than in European American (EA) PCa. Instead, prominent differences in tumor immunobiology between AA vs. EA men were reported in several studies, including a clinical trial with a cancer vaccine, Sipuleucel-T, which AA men had a median nine-month of overall survival advantage over EA men. To mechanistically dissect the immunological and/biological factors that determine tumor cell sensitivity and resistance to immunotherapy of different races, we have developed primary cultures of AA and EA PCa patient-derived tumor organoids, normal organoids, carcinoma associated fibroblasts (CAFs) and benign- associated fibroblasts (BAFs) from many patients and cryopreserved their peripheral blood lymphocytes (PBLs) from the same patient over past years. Our preliminary data show that AA CAFs secrete increased levels of active TGF- in the culture medium than EA CAFs. In addition, we are the first to show that Glycoprotein A repetitions predominant (GARP), the docking receptor for the release of active TGF-β, is over expressed in the adjacent stroma of AA PCa compared to adjacent stroma of EA PCa and AA PCa tissues. Interestingly, the adjacent stroma of AA PCa has increased infiltration of cytotoxic CD8+T cells compared to the adjacent stroma of EA PCa and to the distant stroma of AA PCa, suggesting that immune response is higher in AA stroma but may not be effective due to the increased TGF-β1 and GARP. Our preliminary data of co-culture studies with CAFs and T cells lends further support to the scenario as we observed increased TGF-β1 and reduced IFN-  in these co-cultures. These results suggest that although AA PCa patients may be more responsive to immunotherapies, GARP/TGFβ signaling represents a vulnerable point in AA PCa and may be used as a target for developing more effective immunotherapies. Therefore, we hypothesize that the interaction between tumor and stroma in AA and EA PCa differentially affect the tumor reactivity of T cells and that GARP/TGF-β signaling contribute to the differences in the T cell tumor reactivity among patients. To test the hypothesis, first we will determine whether T cells from AA and EA PCa patients display differences in tumor reactivity in co-cultures with autologous tumor organoids and/or CAFs. Second, our preliminary data have shown that Dabigatran etexilate, an anticoagulant drug for preventing stroke in people with atrial fibrillation, effectively blocks GARP/TGF-1 signaling and that its combination with anti-CTLA4 results in a durable regression of Myc-CaP xenograft tumors. We therefore will determine whether Dabigatran can enhance the anti-PD1/anti-CTLA4’s anti-PCa efficacy in the HiMyc and TRAMP transgenic PCa mouse models. Third, to further enhance the clinical relevance of our study, we will utilize available formalin fixed paraffin embedded tissue blocks from 141 AA and 141 EA matched PCa cases by age and Gleason score and determine the relationship between GARP/TGF-β signaling and various infiltrating immune cells in tumor and stroma of AA and EA PCa. Impact: This proposal capitalizes on the development of unique organoids and cell resources, which allow dissecting factors and mechanisms (i.e. GARP/GARP/TGF-β) signaling leading to immune differences between AA and EA PCa. In addition, a novel strategy for enhancing immune checkpoint therapies in PCa in general and AA PCa in particular may be developed by repurposing Dabigatran etexilate through targeting GARP/TGF-β signaling that is highly activated in the tumor microenvironment of AA PCa, as suggested by our preliminary data. Dabigatran etexilate has shown similar safety profiles or side effects as Aspirin in humans.

项目概要 非裔美国 (AA) 男性的前列腺癌 (PCa) 发病率和死亡率最高 与任何其他种族/族裔人口相比，即使考虑到这些因素，这些差异仍然存在。 失业因素，表明遗传和未知的生物因素可能有助于前列腺癌健康 然而，常见的基因改变，例如 TMPRRSS2-ERG 基因融合和 PTEN 丢失， 发现 AA PCa 中的发生频率远低于欧洲美洲 (EA) PCa。 多项研究报告了 AA 与 EA 男性之间肿瘤免疫生物学的显着差异， 其中包括一项癌症疫苗 Sipuleucel-T 的临床试验，AA 男性的总体接种时间中位数为 9 个月 比 EA 人有生存优势。 机械地剖析决定肿瘤细胞敏感性的免疫学和/生物学因素 以及不同种族对免疫治疗的抵抗力，我们开发了 AA 和 EA PCa 的原代培养物 患者来源的肿瘤类器官、正常类器官、癌相关成纤维细胞 (CAF) 和良性类器官 来自许多患者的相关成纤维细胞（BAF）并冷冻保存其外周血淋巴细胞 （PBL）来自过去几年的同一位患者。 我们的初步数据表明，AA CAF 在培养物中分泌的活性 TGF-β 水平增加 此外，我们是第一个证明糖蛋白 A 重复占主导地位的人。 (GARP) 是释放活性 TGF-β 的对接受体，在邻近基质中过度表达 AA PCa 与 EA PCa 和 AA PCa 组织的相邻基质相比。 与 EA PCa 的邻近基质相比，AA PCa 增加了细胞毒性 CD8+T 细胞的浸润，并且 AA PCa 的远处基质，表明 AA 基质中的免疫反应较高，但可能并非如此 由于 TGF-β1 和 GARP 的增加，我们与 CAF 共培养研究的初步数据有效。 当我们观察到 TGF-β1 增加和 IFN-减少时，T 细胞进一步支持了这种情况。  在这些共文化中。 这些结果表明，尽管 AA PCa 患者可能对免疫疗法更敏感， GARP/TGFβ 信号传导代表 AA PCa 中的一个脆弱点，可用作开发的靶点 因此，我们发现肿瘤和基质之间的相互作用。 AA 和 EA PCa 对 T 细胞的肿瘤反应性有不同影响，并且 GARP/TGF-β 信号传导 导致患者之间 T 细胞肿瘤反应性的差异。 为了检验这一假设，首先我们将确定来自 AA 和 EA PCa 患者的 T 细胞是否表现出 与自体肿瘤类器官和/或 CAF 共培养时肿瘤反应性的差异。 初步数据表明，达比加群酯是一种预防中风的抗凝药物 房颤时，有效阻断 GARP/TGF-β1 信号传导，并且与抗 CTLA4 组合 导致 Myc-CaP 异种移植肿瘤的持久消退，因此我们将确定是否会发生这种情况。 达比加群可以增强 HiMyc 和 TRAMP 转基因中抗 PD1/抗 CTLA4 的抗 PCa 功效 第三，为了进一步增强我们研究的临床相关性，我们将利用现有的模型。 福尔马林固定石蜡包埋的组织块来自 141 例 AA 和 141 例 EA 匹配的 PCa 病例（按年龄和年龄） Gleason评分并确定GARP/TGF-β信号传导与各种浸润免疫之间的关系 AA 和 EA PCa 的肿瘤和基质中的细胞。 影响：该提案利用了独特的类器官和细胞资源的开发， 允许剖析导致免疫差异的因素和机制（即 GARP/GARP/TGF-β）信号 AA 和 EA PCa 此外，还有一种增强 PCa 免疫检查点疗法的新策略。 一般药物和特别是 AA PCa 可以通过靶向重新利用达比加群酯来开发 GARP/TGF-β 信号传导在 AA PCa 的肿瘤微环境中高度激活，如 我们的初步数据显示，达比加群酯的安全性或副作用与阿司匹林相似。 在人类中。