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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要胰腺导管腺癌（PDAC）患者的预后很差。不幸的是，尝试迄今为止，使用单一药物对 PDAC 进行免疫治疗尚未取得显着的临床益处。这很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）的免疫启动可能最终成为有效抗肿瘤免疫的限速屏障。虽然胰腺癌的研究重点一直是原发病期间的 TME，但我们只现在意识到原发性疾病和转移性疾病之间 TME 的差异有多么显着和/或不同器官的转移病灶。这些差异至关重要，因为大多数免疫治疗药物这些方法正在难治性转移性 PDAC 患者中进行测试。我们将在通过确定转移性疾病部位对 PDAC 的不同影响来了解转移性 PDAC 生物学 CDC 的免疫启动。 cDC 是产生肿瘤抗原特异性 T 细胞反应的核心。在动物中模型和人类相关研究中，CDC 对于细胞毒性和检查点的反应至关重要免疫疗法。我们发表的数据显示，PDAC 患者的 cDC 功能严重失调，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 患者的 cDC 受损骨髓发育不良，导致循环前 DC 功能衰竭，交叉呈递受损肿瘤抗原和对检查点抑制剂的反应不佳。即使 DC 开发尚未完成如果 CDC 完全受损，我们已经证明 CDC 功能失调并被排除在 PDAC TME 之外。总体而言，这些机制削弱了传统疗法引发肿瘤抗原特异性 T 细胞反应的能力，检查点免疫疗法以提高疗效。这些数据共同支持了我们的假设，即转移性器官位点特异性驱动因素会对局部和全身肿瘤免疫产生不同的影响。我们将直接解决这一假设的目的如下：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. 确定治疗如何对不同转移部位的 TME 进行差异化塑造以产生影响免疫启动。意义：这些理解对于 mPDAC 患者的治疗至关重要。