Abstract B004: IgG-Fcγ activating receptor signaling slows tumor progression in a genetically engineered mouse model of pancreatic cancer

Abstract

Our previous work demonstrates that KPC mice deficient in class-switched antibodies (AID-/-), but not IgM (μS-/), exhibit accelerated pancreatic tumor progression. Furthermore, IgG antibodies, which are abundant within the pancreatic tumor microenvironment, co-localize with stromal fibroblasts and macrophages, suggesting direct interactions within the stroma. Loss of IgG in AID-deficient mice reprograms macrophages to a mixed M1/M2 phenotype and reduces both T-cell infiltration and the number of tumor-associated podoplanin-expressing fibroblasts. These findings indicate a novel role for class-switched antibodies in modulating stromal biology and pancreatic tumor progression. Based on our previous findings we anticipate that global genetic ablation of activating FcγR1 and/or FcγR3 signaling pathways in KPC mice will accelerate pancreatic tumorigenesis through disruption of novel stromal IgG-FcγR signals necessary for both ECM homeostasis and stromal immune responses. To determine whether IgG-Fcγ receptor signaling pathways are critical in this process, we bred Pdx1-Cre;LSL-KrasG12D;Tp53Fl/+ mice with B6.129P2-Fcer1g tm1Rav and B6.129P2- Fcgr2b tm1TtK N12 mice for 10 generations. Mice were evaluated for tumor progression and survival by gross and histologic analysis. Genetic deficiencies in both activating (disrupting both FcγR1 and FcγR3 signaling) and inhibitory (FcγR2B signaling) Fcγ receptor pathways accelerated pancreatic tumor formation and lethality in this model. Data presented here represent preliminary findings regarding the importance of Fcγ receptor signaling in progression on KrasG12D-driven pancreatic cancer in the KPC mouse model. These findings indicate the importance of FcγR receptor signaling, which occurs in a wide array of cell lineages, including immune, epithelial, endothelial, and fibroblast populations, in delaying KrasG12D-driven pancreatic cancer. Given the complexity of FcγR signaling pathways and their biological outputs across different cell types, fully elucidating these pathways will require conditional deficiencies to understand the nuanced cell-specific biology.