The Impact of Metastatic Site On Dendritic Cell-Driven Tumor Immunity

转移部位对树突状细胞驱动的肿瘤免疫的影响

• 批准号: 10738428
• 负责人: David G DeNardo
• 金额: $ 65.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738428
• 关键词: Address; Animal Model; Atlases; Biological Models; Biology; Bone Marrow; Cells; Clinical; Correlative Study; Cross Presentation; Data; Dendritic Cells; Development; Disease; Exclusion; Functional disorder; Genetic; Genomics; Goals; Human; Imaging Techniques; Immune; Immune checkpoint inhibitor; Immunity; Immunology; Immunotherapeutic agent; Immunotherapy; Impairment; Infiltration; Institution; Lead; Limes; Link; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Nature; Neoplasm Metastasis; Organ; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Primary Neoplasm; Prior Therapy; Process; Productivity; Prognosis; Publishing; Refractory; Reporting; Research; Sampling; Shapes; Site; Stromal Cells; T cell infiltration; T cell response; Testing; Tissue Banks; Tissue Model; Tissue Sample; Tumor Antigens; Tumor Biology; Tumor Immunity; checkpoint therapy; chemotherapy; conventional therapy; cytotoxic; density; human tissue; mouse model; multiple omics; programs; prospective; response; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately, attempts at immunotherapy for PDAC to date using single agents have not achieved significant clinical benefits. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME). Our recent data suggest that immune priming by dendritic cells (cDCs) may ultimately a rate-liming barrier to productive anti-tumor immunity. While the focus of research in pancreatic cancer has been on the TME during primary disease, we are only now realizing how significant the differences in the TME are between primary and metastatic disease and/or metastatic lesions in different organs. These differences are critical, as the majority of immunotherapeutic approaches are being tested in refractory metastatic PDAC patients. We will address this shortcoming in understanding metastatic PDAC biology by determining the differential impact of metastatic disease site(s) on immune priming by cDCs. cDCs are central for generating tumor antigen-specific T-cell responses. In animal models and human correlative studies, cDCs are crucial for responsiveness to both cytotoxic and checkpoint immunotherapies. Our published data show that cDCs were severely dysfunctional in PDAC patients and that this dysfunction was driven by two distinct mechanisms. First, we reported that PDAC patients had impaired cDC development in their bone marrow, which led to a functional depletion of circulating pre-DCs, impaired cross-presentation of tumor antigens, and poor responses to checkpoint inhibitors. Even when DC development is not fully impaired, we've shown cDCs are dysfunctional and excluded from the PDAC TME. Overall, these mechanisms impair the ability of conventional therapies to prime tumor antigen-specific T-cell responses and checkpoint immunotherapy to drive efficacy. Together these data support our hypothesis that metastatic organ site-specific drivers lead to divergent effects on local and systemic tumor immunities. We will directly address this hypothesis with the following aims: Aim 1. Determine the impacts of the site of metastatic disease on immune priming by cDCs. Aim 2. Determine the impacts of the site of metastatic disease on systemic immunity and cDC development. Aim 3. Determine how therapy differentially shapes the TME at different metastatic sites to impact immune priming. Significance: These understandings are critical for the treatment of mPDAC patients.

项目摘要/摘要 胰腺导管腺癌（PDAC）患者的预后很沮丧。不幸的是，尝试 PDAC使用单一药物的免疫疗法尚未获得明显的临床益处。这可能是 由于存在独特的抑制性肿瘤微环境（TME）。我们最近的数据表明 树突状细胞（CDC）的免疫启动最终可能是生产性抗肿瘤免疫的速率限制障碍。 虽然胰腺癌研究的重点一直是原发性疾病期间的TME，但我们只是 现在意识到TME在原发性疾病和/或转移性疾病之间的差异有多大 不同器官中的转移性病变。这些差异至关重要，因为大多数免疫治疗性 在耐火转移性PDAC患者中正在测试方法。我们将解决这个缺点 通过确定转移性疾病部位对转移性PDAC生物学的了解 CDC的免疫启动。 CDC是产生肿瘤抗原特异性T细胞反应的中心。在动物中 模型和人类相关研究，CDC对于对细胞毒性和检查点的反应至关重要 免疫疗法。我们发表的数据表明，PDAC患者的CDC严重功能失调，并且 这种功能障碍是由两种不同的机制驱动的。首先，我们报道PDAC患者受损CDC 骨髓的发育导致循环前DC的功能耗竭，跨表达受损 肿瘤抗原，对检查点抑制剂的反应不佳。即使DC开发不是 完全受损，我们显示了CDC功能失调，并将其排除在PDAC TME之外。总体而言，这些 机制损害了常规疗法素抗原特异性T细胞反应的能力和 检查点免疫疗法以提高功效。这些数据共同支持我们的假设转移器官 特定地点驱动因素会对局部和全身性肿瘤免疫产生不同的影响。我们将直接 以以下目的解决这一假设： 目标1。确定转移性疾病部位对CDC免疫启动的影响。 目标2。确定转移性疾病部位对全身免疫和CDC的影响 发展。 目标3。确定治疗如何在不同转移性部位差异塑造TME以影响 免疫启动。 意义：这些理解对于治疗MPDAC患者至关重要。