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: 10538647
• 负责人: Anshu Agrawal
• 金额: $ 35.17万
• 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/10538647
• 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; Disparity; Dissection; Distant; Docking; ERG gene; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Ethnic Population; 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; 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; TGFB1 gene; Testing; Tissue Embedding; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Tumor Escape; Tumor-Derived; 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; immune cell infiltrate; improved outcome; individual patient; men; mortality; mouse model; neoplastic cell; novel strategies; overexpression; prostate cancer progression; 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.

项目摘要 前列腺癌（PCA）发病率和死亡率是非裔美国人（AA）男性的最高 与任何其他种族/族裔人口相比。这些差异仍在考虑到 社会经济因素，表明遗传学和未知生物学因素可能有助于PCA健康 差异。然而，常见的遗传改变，例如TMPRRSSS2-erg基因融合和PTEN损失， 发现在AA PCA中，发生的频率要比欧美（EA）PCA少得多。反而， 在几项研究中报道了AA与EA男性之间肿瘤免疫生物学的显着差异， 包括与癌症疫苗Sipuleucel-T进行的临床试验，AA男性中间为9个月的中间 比男人的生存优势。 为了机械解剖确定肿瘤细胞灵敏度的免疫学和/生物学因素 以及对不同种族免疫疗法的抵抗，我们开发了AA和EA PCA的主要培养物 患者衍生的肿瘤器官，正常的器官，癌相关的成纤维细胞（CAF）和良性 - 许多患者的相关成纤维细胞（BAF）和冷冻保存其外周血液淋巴细胞 （PBL）在过去几年中来自同一患者。 我们的初步数据表明，AA CAFS秘密在培养中提高了主动TGF-的水平 中等比EA CAFS。此外，我们是第一个证明糖蛋白A重复的人 （GARP）是释放活性TGF-β的对接受体，在相邻的基质中过度表达 与EA PCA和AA PCA组织的邻近基质相比，AA PCA的。有趣的是，相邻的基质 与EA PCA的邻近基质相比，AA PCA的细胞毒性CD8+T细胞的浸润增加了 AA PCA的遥远基质，表明AA基质中的免疫反应较高，但可能不是 由于TGF-β1和GARP的增加，有效。我们与CAF共同文化研究的初步数据 随着我们观察到TGF-β1的增加并减少了IFN-，T细胞向情景提供了进一步的支持 在这些共同文化中。 这些结果表明，尽管AA PCA患者可能对免疫疗法更敏感，但 GARP/TGFβ信号传导代表AA PCA中的一个脆弱点，可以用作发展的目标 更有效的免疫疗法。因此，我们假设肿瘤与基质之间的相互作用 在AA和EA中 导致患者T细胞肿瘤反应性的差异。 为了检验假设，首先我们将确定来自AA和EA PCA患者的T细胞是否显示 自体肿瘤器官和/或CAF的共培养中肿瘤反应性的差异。第二，我们的 初步数据表明，达比加氏酶Etexilate，一种抗凝药，用于预防人中风的中风 使用心房颤动，有效地阻止了GARP/TGF-1信号传导，并且与抗CTLA4的结合 导致MYC-CAP特征肿瘤的持久回归。因此，我们将确定是否 dabigatran可以增强抗PD1/抗CTLA4在HIMYC和TRAMP转基因中的抗PCA效率 PCA鼠标模型。第三，为了进一步增强我们研究的临床相关性，我们将利用可用的 福尔马林固定石蜡嵌入的组织块中的141个AA和141 EA与PCA病例相匹配， 格里森评分并确定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：该提案大写了独特的器官和细胞资源的发展， 允许解剖因素和机制（即GARP/GARP/TGF-β）信号传导导致免疫差异 在AA和EA PCA之间。此外，一种增强PCA免疫检查点疗法的新型策略 尤其是一般和AA PCA，可以通过重新利用dabigatran来开发。 GARP/TGF-β信号在AA PCA的肿瘤微环境中高度激活，如 我们的初步数据。 dabigatran Etexilate表现出与阿司匹林相似的安全性或副作用 在人类中。