Abstract PR14: Preclinical models to dissect immune escape in pancreatic cancer
Authors: Freed-Pastor William A. , Lambert Laurens , Garcia Ana P. , Eng George , Yilmaz Omer , Jacks Tyler 
Published: March 2020

Abstract
Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis and efforts to harness immune-based therapies are in high demand. Using retrograde pancreatic duct instillation of lentiviral particles, we have established and characterized a preclinical autochthonous mouse model for immunogenic PDAC. Specifically, pancreatic tumors are initiated in KRASLSL-G12D/+; p53flox/flox (KP) mice using lentiviral particles expressing Cre recombinase and a tumor-specific antigen (TSA) to track the endogenous antigen-specific T cell response in both precursor lesions (PanIN) and adenocarcinoma (PDAC). Using this model system, we demonstrate profound immunoediting in the autochthonous pancreas, which occurs primarily at the preinvasive (PanIN) stage. In parallel, we derived a biologic library of immunogenic or nonimmunogenic pancreatic organoids and developed an ex vivo co-culture system of pancreatic organoids with antigen-specific CD8 T cells that recapitulates the phenomena of immunoediting. Additionally, we examined the effect of TSA expression in established adenocarcinomas and performed preclinical trials in which the CD8 T-cell compartment was transiently depleted and then restored, to evaluate at what point during tumor progression pancreatic tumors gain the ability to evade immune clearance. Intriguingly, we identified both “regressor” tumors as well as “progressor” tumors in response to CD8 restoration. Longitudinal imaging was paired with flow cytometric analysis to track both clinical and antigen-specific T-cell responses. Excitingly, we found that a subset of “regressor” tumors undergo a complete pathologic response following CD8 T-cell restoration, highlighting the translational potential for novel insights regarding immune escape in PDAC. In addition, we demonstrate that both the magnitude and kinetics of the antigen-specific T-cell response tracks with the clinical response of these tumors, with “progressor” tumors eliciting both delayed kinetics and a blunted response compared with “regressor” tumors. Additionally, we developed an immunogenic genetically defined organoid system in which KP organoids were engineered to express a defined neoantigen from a safe harbor locus. In line with prior studies, a subset of immunogenic organoids was completely rejected upon orthotopic transplantation and this clearance was dependent upon CD8 T cells. However, in contrast to observations using two-dimensional monolayer cell lines, we also identified a significant subset of orthotopically transplanted immunogenic pancreatic organoids that successfully evade immune clearance, despite eliciting an antigen-specific immune response. Immunophenotyping the tumor microenvironment revealed that antigen-specific CD8 T cells within these “escaper” tumors display hallmarks of T-cell exhaustion. These complementary systems now provide a robust preclinical platform to rapidly interrogate potential therapeutic interventions.
This abstract is also being presented as Poster C17.
Citation Format: William A. Freed-Pastor, Laurens Lambert, Ana P. Garcia, George Eng, Omer Yilmaz, Tyler Jacks. Preclinical models to dissect immune escape in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR14.