Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Microbiology and Immunology, PhD
Committee Co-Chair (if applicable)
trained immunity; pancreatic cancer; IRE; beta-glucan
Pancreatic cancer (PC) is a challenging diagnosis yet to benefit from advances in immune oncologic treatments. Irreversible electroporation, a non-thermal method of tumor ablation, is used in treatment of select patients with locally advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan-induced trained immunity in the treatment of PC. β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and anti-tumor function after exposure to ablated and un-ablated tumor conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine pancreatic cancer model in WT and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and utilized in combination with IRE to treat PC. The peripheral blood of patients taking oral β-glucan after IRE in human PC patients was evaluated by mass cytometry. IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented anti-tumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The anti-tumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from treatment naïve PC patient. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of stage III locally advanced PC patients who had undergone IRE. These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.
Woeste, Matthew, "Irreversible electroporation potentiates beta glucan induced trained innate immunity: a novel combination treatment for pancreatic adenocarcinoma." (2023). Electronic Theses and Dissertations. Paper 4095.