Abstract C083: Deconvoluting the metastatic PDA tumor microenvironment

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US with a 5-year survival of 11%. Most patients die from disseminated disease, with liver being the most frequently colonized metastatic site. In primary PDA tumors, the tumor microenvironment has been extensively linked to therapy resistance and immune suppression. However, the extent that the microenvironment in the liver metastatic niche promotes immune evasion compared to primary PDA lesions remains unclear. Importantly, strategies to effectively target metastatic disease will provide the most immediate benefit for clinical treatment of PDA. The heterogeneous tumor microenvironment has been recognized as a primary barrier to PDA treatment. Here, the immune and stromal cells are not functioning in a manner beneficial for the host. Numerous cell types have been shown to have a pro-tumor function including regulatory T cells, tumor associated macrophages (TAMs), myeloid derived suppressor cells, and cancer associated fibroblasts (CAFs). Recently, we and others have shown that there are metabolic crosstalk interactions between cancer cells, TAMs, and CAFs. These interactions function to support primary tumor growth, immune suppression, and resistance to chemotherapy. However, the degree that the cancer cell heterogeneity, immune infiltration, and stromal populations present in metastatic lesions mirror primary tumors remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. Using this system, we have identified differential programming among the different cell populations between pancreas and liver PDA lesions using single cell RNA sequencing. Further, we directly compared immune infiltration between primary and metastatic tumors using mass cytometry. Our data indicate alternative mechanisms of immune suppression in liver PDA lesions, which can be directly targeted in combination with checkpoint inhibition strategies. Overall, these data have the potential to lead to new avenues to activate or target the immune system to treat metastatic PDA, an urgent clinical need for pancreatic cancer patients. Citation Format: Rima Singh, Christopher Halbrook, Nina Steele. Deconvoluting the metastatic PDA tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C083.