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.

Project Narrative While the majority of PDAC patients will develop metastatic disease, the organ specific immunology and biology of these metastatic lesions is poorly understood. These understandings are critical for the treatment of metastatic PDAC patients. This proposal will study the impact of metastatic disease on dendritic cells using human patient samples and model systems.