Date on Master's Thesis/Doctoral Dissertation

5-2021

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Yan, Jun

Committee Member

Egilmez, Nejat

Committee Member

Bodduluri, Haribabu

Committee Member

Jala, Venkatakrishna

Author's Keywords

Trained immunity; pancreatic cancer; immunotherapy; beta glucan; innate immunity; myeloid

Abstract

Despite the success of immunotherapy in many types of cancer, pancreatic adenocarcinoma (PDAC) has yet to benefit. Innate immune cells are critical to antitumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Though trained innate immunity has mostly been investigated in the context of infection, the induction of trained innate immunity could also protect against tumors, and specifically pancreatic tumors. Here, we demonstrate that yeast-derived particulate β-glucan, a known inducer of trained immunity, traffics to the pancreas following IP administration. This causes a CCR2-dependent influx of newly characterized monocytes/macrophages to the pancreas which display features of trained immunity. These trained cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced phagocytosis and ROS-mediated cytotoxicity against pancreatic tumors. In orthotopic models of pancreatic cancer, mice trained with β-glucan show reduced tumor burden and prolonged survival which is further enhanced when combined with anti-PD-L1 immunotherapy. Cumulatively, these findings not only add novel characterization to the dynamic mechanisms, scope and localization of peripheral trained immunity, but also identify a direct application of trained immunity to cancer that can be utilized directly within the pancreas to reprogram the immunologically cold tumor microenvironment of PDAC.

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