Rahma Tariq
Research Mentor: Yaqing Zhang
Mentor Department: Surgery, Medicine
Author(s): Rahma Tariq, Shruti Gupta, Olivia Yang, Wei Yan, Kristee Brown, Megan Procario , Marina Pasca di Magliano , Yaqing Zhang
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 60
Abstract
Pancreatic ductal adenocarcinoma (PDA) is the most common and aggressive form of pancreatic cancer, known for its tendency to be diagnosed at advanced stages and high mortality rate. PDA is resistant to common therapy, and there are currently no good options to treat it due to the immunosuppressive nature of its tumor microenvironment (TME) that is characterized by cancer-associated fibroblasts and immune-suppressive myeloid cells. This project aimed to identify potential therapeutic targets within PDA’s immunosuppressive TME through the use of genetically engineered mouse models. FSF-KRASG12D and Ptf1a-FLPO systems were specifically utilized to express the oncogenic form of KRAS, the major mutant gene of PDAC caused by a G12D mutation, in pancreatic epithelial cells. In addition, through the use of LysM-Cre and Flox/flox (fl/fl) mouse models, we were able to target genes important for immune responses, such as Immune Responsive Gene 1(IRG1), specifically in LysM expressing myeloid cells. With this dual recombinase mouse model Ptf1aFlpO; KrasFSF-G12D/+; LysMcre;Irg1fl/fl(KFLI), we sought to investigate the therapeutic potential of targeting IRG1 during pancreatic carcinogenesis. We observed similar intraepithelial neoplasia (PanIN), the most common form of PDA precursor lesions, in both KFLI and control KFL mice. However, immunostaining showed alteration of the TME with increased CD8 T cell infiltration and decreased immunosuppressive factor Arginase 1 upon the loss of IRG1. We also established an orthotopic mouse model of PDA by injecting the PDA cell line 7940B into the pancreas of LysMcre;Irg1fl/fl mice and observed a reduced tumor size in comparison to the control mice. In addition, CD8 T cell depletion rescued the tumor growth in the LysMcre;Irg1fl/fl mice. In conclusion, ablating the IRG1 gene results in the manipulation of the TME of this KRAS driven spontaneous cancer model and relieves immunosuppression in the orthotopic model of PDA.
