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

项目总结/摘要 胰腺导管腺癌（PDAC）患者的预后很差。不幸的是， 迄今为止，使用单一药剂的PDAC免疫疗法尚未获得显著的临床益处。这很可能 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）的免疫引发可能最终成为产生抗肿瘤免疫的限速屏障。 虽然胰腺癌研究的重点一直是原发性疾病期间的TME，但我们仅 现在意识到原发性和转移性疾病之间TME的差异有多么显著，和/或 不同器官的转移性病变。这些差异是至关重要的，因为大多数免疫系统 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生物学的不同影响， 通过cDC的免疫引发。cDC是产生肿瘤抗原特异性T细胞应答的核心。在动物 模型和人类相关研究中，cDC对于细胞毒性和检查点两者的应答性至关重要。 免疫疗法我们发表的数据显示，PDAC患者中的cDC严重功能障碍， 这种功能障碍由两种不同的机制驱动。首先，我们报道了PDAC患者的cDC受损， 在他们的骨髓中的发育，这导致循环前DC的功能耗尽，损害了交叉呈递， 以及对检查点抑制剂的不良反应。即使DC开发不是 在完全受损的情况下，我们已经表明cDC功能失调并被排除在PDAC TME之外。总的来说，这些 机制削弱了常规疗法引发肿瘤抗原特异性T细胞应答的能力， 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 位点特异性驱动因子导致对局部和全身肿瘤免疫的不同影响。我们会直接 处理这一假设的目的如下： 目标1。确定转移性疾病的部位对cDC的免疫引发的影响。 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部位对TME进行差异化塑造， 免疫启动 意义：这些理解对于mPDAC患者的治疗至关重要。

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.