Abstract 5373: Decoding the role of intrinsic pancreatic cellular signaling in shaping the immunosuppressive tumor microenvironment

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among major cancers, with over 50% of patients having liver metastases at diagnosis. Conventional T-cell-based immunotherapies are ineffective against PDAC liver metastases due to the intricate hepatic tumor microenvironment (TME) that hinders effective immune responses. Thus, it is vital to promote the influx of cytotoxic lymphocytes and prime antitumor immunity. PDAC cells exhibit plasticity and intrinsic cellular heterogeneity, leading to varying immune cell infiltrates and immune responses. Concurrently, early metastases to the liver create an immunosuppressive environment. Our study employs multiple PDAC models, originating from a congenic array of distinct PDAC cell clone tumors with varying degrees of T cell infiltration to delineate the signaling pathways that lead to immunosuppression in the pancreas and liver. Methods: The compendium of congenic PDAC murine cell clones mirrors immune heterogeneity observed in tumors, spanning from low to high T cell infiltration. To overcome a scarcity of tumor-specific neoepitopes in PDAC, we engineered PDAC cell clones expressing chicken ovalbumin (OVA) for antigen-specific T and B cell responses. By subcutaneous and intraportal vein injection of PDAC cell clones into mice, we induce primary pancreatic and metastatic liver tumors to explore immune phenotypes and assess anti-tumor adaptive immune responses, including myeloid and lymphoid cell subsets. Results: In vivo engraftment of PDAC clones showed varied CD4+/CD8+ T cells and polymorphonuclear myeloid-derived suppressor cells, accentuated with immunogenic OVA antigen expression. While all OVA+ PDAC lines elicited antigen-specific immune responses, only ‘TIL high’ tumors were eradicated, while ‘TIL low’ clones persisted in vivo. Additionally, ‘TIL low’ clones formed liver metastases upon intraportal injection, despite OVA expression. RNAseq unveiled differential expression in IL-1 family cytokines and receptors, chemokine-like factor gene superfamily, parathyroid hormone relevant function and metabolism. Current investigations include altering these pathways to re-program the tumor microenvironment and induce local immune suppression. Conclusion: Using diverse PDAC models, we created tumors with immune heterogeneity and altered transcriptional profiles. We identified validated differentially expressed immune altering cytokines, such as CXCL1 and CSF3, and potential novel IL-1 family genes and parathyroid signaling genes. The altered TME conferred protection against tumor antigen-specific immunity in certain clones, both in subcutaneous and liver metastasis models. Ongoing studies will assess the impact of these genes in the distinct environments, offering avenues for immunotherapeutic strategies targeting pancreatic cancer liver metastasis. Citation Format: Bushangqing Liu, Ethan Agritelley, Daniel Nussbaum, Junping Wei, Gangjun Lei, Melissa Gajda, Zachary Hartman. Decoding the role of intrinsic pancreatic cellular signaling in shaping the immunosuppressive tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5373.