Date on Master's Thesis/Doctoral Dissertation

5-2023

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Yan, Jun

Committee Co-Chair (if applicable)

Bodduluri, Haribabu

Committee Member

Jala, Venkatakrishna

Committee Member

Zhang, Huang-Ge

Committee Member

Chesney, Jason

Committee Member

McMasters, Kelly

Author's Keywords

trained immunity; pancreatic cancer; IRE; beta-glucan

Abstract

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.

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