Abstract 7465: Leukemia inhibitory factor creates an immune suppressive tumor microenvironment and fosters tumor growth in KRAS-driven pancreatic ductal adenocarcinoma
Authors: Miller-Phillips Lisa , Hanafi Imene Boukhalfa , Combes Alexis J. , Bano Shabana , Hysenaj Lisiena , Roose Jeroen P. , Olshen Adam , Kiemen Ashley , Umetsu Sarah , Wang Man-Tzu , Collisson Eric A. 
Published: March 2024

Abstract
Immune checkpoint blockade revolutionized cancer treatments by activating anti-tumor immunity. Pancreatic ductal adenocarcinoma (PDA) patients have not benefited from these advances due to an immune suppressive tumor microenvironment. Identifying PDA cell-encoded factors that drive immune evasion is necessary to unlock new immunologically active treatment options in PDA. We have recently demonstrated that the cytokine Leukemia inhibitory factor (LIF) is highly upregulated in PDA compared to the normal healthy pancreas. LIF is known for its immune suppressive qualities, but data on LIF in PDA is currently limited. We generated a conditional Lif flox (L) allele and crossed it into the well-established KrasLSL-G12D/+, Trp53flox/flox, Pdx1-Cre (KPC) mouse model. LKPC mice (n=29) had longer overall survival (69 days) than control KPC mice (n=29) (59 days), (p&lt;0.05). LKPC mice harbored significantly smaller tumors with an average tumor weight of 0.6g compared to KPC control animals with an average tumor weight of 1.0g (p&lt;0.005). Immunohistochemical evaluation of tumor proliferation measured by Ki-67 positivity in LKPC and KPC tumors at endpoint showed comparable results. Tumor-derived cell lines from KPC and LKPC mice showed no growth differences in vitro nor when reimplanted subcutaneously (sc) in immunodeficient mice. In contrast, we observed a significant decrease in tumor growth and weight in LKPC sc tumors (p&lt;0.05) compared to the KPC sc tumors in syngeneic mice. LKPC sc tumors had significantly fewer neutrophils and more macrophages, particularly MHC II-high macrophages, known for their anti-tumor qualities when compared to KPC sc tumors using flow cytometry. A trend towards more CD8+ T-cells in sc LKPC tumors was also observed. Our genetically engineered mouse model confirmed this finding by immunohistochemical evaluation of tumors at endpoint, which demonstrated a significant increase of CD8+ T-cells in the LKPC animals compared to the KPC controls. In summary, we find that cancer-cell-expressed LIF augments tumor growth and shortens overall survival by changing the immune tumor microenvironment, nominating leukemia inhibitory factor depletion as a promising therapeutic immune target in KRAS-driven pancreatic cancer.
Citation Format: Lisa Miller-Phillips, Imene Boukhalfa Hanafi, Alexis J. Combes, Shabana Bano, Lisiena Hysenaj, Jeroen P. Roose, Adam Olshen, Ashley Kiemen, Sarah Umetsu, Man-Tzu Wang, Eric A. Collisson. Leukemia inhibitory factor creates an immune suppressive tumor microenvironment and fosters tumor growth in KRAS-driven pancreatic ductal adenocarcinoma [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(6_Suppl):Abstract nr 7465.