Abstract Pancreatic cancer is the third leading cause of cancer-related deaths in the U.S. and is most frequently diagnosed between the ages of 65-74 years. Only 11.5% of patients are expected to survive 5 years after diagnosis. There is extensive evidence that tumor microenvironment (TME) plays a critical role in cancer progression and metastasis. Despite the fact that most patients are diagnosed over the age of 60, most preclinical murine tumor models utilize young, healthy, adolescent mice, failing to account for structural and/or functional changes in stroma and immune cells that occur in tissues over time and contribute to tumor progression. Marked differences in lifespan between mice and humans preclude natural development of many age-related physiologic changes in mice that occur in humans over the course of decades. We performed a pilot study to test our hypothesis that KPC pancreatic tumors grown orthotopically in the pancreas of genetically engineered, C57BL/6-Tg (LMNA*G608G) HClns/J mice, a model of Hutchinson-Gilford progeria syndrome with features of accelerated aging, would have altered tumor growth in comparison to tumors in age-matched wild type controls. We found that tumor growth in LMNA mice outpaced that of WT mice. Quantitative digital image analysis showed significantly reduced intratumoral infiltration of CD45+ leukocytes in LMNA mice in comparison to WT (p=0.0098). There was a significant reduction in tumor-infiltrating CD3+ T cells (p=0.038) and F4/80+ macrophages (p=0.0102). Our data supports the hypothesis that functional, age-related, immune and/or stromal changes in the TME impact pancreatic tumor growth and progression. Innovative strategies that better model age-related changes in the TME may better recapitulate the aggressive course of pancreatic cancer in aged patients. Citation Format: Morgan M. Green, Tara Fujimoto, Cullen Taniguchi, Natalie Fowlkes. Modeling age-related changes in the tumor microenvironment in an orthotopic immunocompetent murine pancreatic cancer model - a novel approach. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5191.
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