Research Project Pancreatic Cancer

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PROJECT 2 (PANCREAS) SUMMARY The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately, attempts at immunotherapy for PDAC to date have not achieved significant clinical benefits. It is widely accepted that radiation therapy (RT) can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals, and this immune priming effect has a crucial role in RT efficacy in multiple cancer types. In contrast, combining RT with checkpoint immunotherapy has been generally underwhelming in PDAC. It is unclear if this reflects an inability of RT to prime tumor-specific T cells or a need for additional stimulants that are supportive of T-cell priming. Dendritic cells (cDCs) are central for generating tumor antigen-specific T-cell responses. In animal models and human correlative studies, cDCs are crucial for responsiveness to checkpoint immunotherapy and RT-induced tumor immunity. Our hypothesis is that RT drives divergent effects on local and systemic tumor immunities through regulation of cDCs. We will directly address this hypothesis, focusing on how DCs and T-cell responses are co-shaped during SOC RT. We will use a combination of scRNAseq, spatially resolved protein, metabolomic profiling in human PDAC tissues and mouse models to test the following. In Aim 1, we will determine the local and systemic impacts of RT on local immune priming by cDCs. These studies will use a combination of longitudinally collected human tissues from patients undergoing SBRT and genetically engineered mouse models (GEMMs) to assess the impact of RT on DC phenotype and function. Leveraging our institutional strengths, we will conduct these studies in three cohorts of prospective and retrospective tissue collections from human PDAC patients receiving SBRT and conduct mechanistic studies using PDAC GEMMs. These studies will assess the local impact of SBRT on cDC function. In Aim 2, we will determine the impact of RT on cDC differentiation and systemic immunity in PDAC patients. Our data in both human PDAC patients and mouse models demonstrated that key differences in myelopoiesis and cDC development in PDAC can impair tumor immunity. Furthermore, our preliminary data indicated that SBRT could alter cDC development and phenotype. In this aim, we will use a combination of human tissues and GEMMs to specifically study how RTs impact systemic DC development, phenotype and function, and the net impact this has on tumor immunity and T-cell priming in response to RT. In Aim 3, we will determine the impact of RT on interactions between regional metabolism and cDC-directed T-cell immunity. RT can have a dramatic impact on tumor and stromal cell metabolism. In parallel, these metabolic changes can regulate cDC and T-cell survival and function. However, these interactions have not been well studied in the context of intact PDAC tissues, where regional heterogeneity in immune infiltrate, hypoxia, and stromal density are dominant players. We will therefore use multiple orthogonal approaches including CODEX, NIMS, and advanced imaging of human PDAC tissues to spatially resolve the impact of SBRT on subregional heterogeneities in cellular immunity, stromal composition, and metabolic profiles.